Absorption, distribution, metabolism, and excretion of pritelivir in both trials

“Two human mass balance trials (a multiple-dose trial and a single-dose trial) were performed to characterize the absorption, distribution, metabolism, and excretion of 100 mg oral pritelivir combined with a single microdose of 14C-pritelivir.” (opens the source at this quote in a new tab)
“This publication describes the results of 2 open-label mass balance trials after single and multiple oral doses of unlabeled pritelivir (100 mg) combined with a single microdose of 14C-labeled pritelivir at the start of the PK blood collection period in healthy male subjects to characterize the absorption, distribution, metabolism, and excretion of pritelivir, to identify its metabolites, and to describe the PK of pritelivir and its metabolites.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: mass balance and metabolite profile after multiple doses

“Trial 1. This was an open label, single-center trial to investigate the mass balance and metabolite profile of pritelivir after multiple doses in healthy male subjects.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: mass balance and metabolite profile after a single dose

“Trial 2. This was an open label, single-center trial to investigate the mass balance and metabolite profile of pritelivir after a single dose in healthy male subjects.” (opens the source at this quote in a new tab)

Purpose of a human mass balance trial

“In human mass balance trials, the administration of a radiolabeled drug is used to gather information on the absorption, distribution, and routes of elimination.” (opens the source at this quote in a new tab)

Trial sites of AIC316-01-I-04 and AIC316-03-I-02

“Trial 1 was conducted at Hammersmith Medicines Research (London, UK) and Trial 2 was conducted at PRA Health Sciences (Groningen, The Netherlands).” (opens the source at this quote in a new tab)

Ethics committees and conduct standards in both trials

“Both trial protocols and amendments were approved by an ethics committee.” (opens the source at this quote in a new tab)
“Trial AIC316-01-I-04 (further described as Trial 1) was approved by the Independent Ethics Committee Plymouth, United Kingdom and Trial AIC316-03-I-02 (further described as Trial 2) was approved by the Independent Ethics Committee, METC Stichting BEBO Assen, The Netherlands.” (opens the source at this quote in a new tab)
“Independent Ethics Committee-approved written informed consent was obtained from each subject prior to the start of the trial.” (opens the source at this quote in a new tab)
“The trials were conducted in accordance with ethical principles that have their origins in the Declaration of Helsinki, Good Clinical Practice (GCP), International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines, and applicable laws and regulations.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: open-label, single-center, multiple-dose design

“Trial 1. This was an open label, single-center trial to investigate the mass balance and metabolite profile of pritelivir after multiple doses in healthy male subjects.” (opens the source at this quote in a new tab)
“Eight subjects received a single oral dose of 500 mg pritelivir on day 1, followed by 7 daily oral doses of 100 mg (days 2-8).” (opens the source at this quote in a new tab)
“On day 8 the oral dose was spiked with 3 μg (9.3 kBq) of 14C-pritelivir, labeled at the pyridinyl phenyl acetic moiety (Figure 1).” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: steady-state conditions and the loading dose

“The first trial (Trial 1) was performed under steady-state conditions, which were reached after administration of an oral loading dose of 500 mg pritelivir on day 1, followed by 7 daily oral doses of 100 mg, which was in line with the clinical dose tested in phase 3 (100 mg once daily following a loading dose of 400 mg).” (opens the source at this quote in a new tab)
“The oral loading dose was used to reach steady state more quickly as pritelivir is known to have a long half-life (52-83 hours).” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: screening, confinement, and follow-up

“For each subject, the screening examination took place within 21 days before the first dose of trial mediation.” (opens the source at this quote in a new tab)
“Subjects were hospitalized from day 1 until day 34 and returned to the clinic for a follow-up visit between day 37 and day 44 (29-36 days after the last dose) (Figure 2).” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: blood sampling schedule

“Blood samples (3 mL at each time point) for PK analysis of pritelivir were collected predose from day 1 until day 8 and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48, 60, 72, 96, 120, 144, 168, 192, 216, 240, 288, and 336 hours postdose on day 8.” (opens the source at this quote in a new tab)
“Blood samples (3 mL at each time point) for PK analysis of total radioactivity (TRA) were collected predose on day 1 and day 8, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48, 96, 144, 192, 240, 288, 336, 384, 432, 480, 528, 576, and 624 hours postdose on day 8.” (opens the source at this quote in a new tab)
“Blood samples (10 mL each time point) for metabolite profiling were collected at 2, 4, 24, 48, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 624 hours postdose on day 8.” (opens the source at this quote in a new tab)
“Metabolite profiling was done using pooled plasma samples (0-24 hours).” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: urine and feces collection schedule

“Urine and feces were collected to determine the recovery of TRA and for the identification of metabolites.” (opens the source at this quote in a new tab)
“Urine was collected predose on days 1 and 8 and postdose on day 8 between 0-4, 4-8, 8-12, 12-24, 48-96, 96-144, 144-192, 192-240, 240-288, 288-336, 336-384, 384-432, 432-480, 480-528, 528-576, and 576-624 hours.” (opens the source at this quote in a new tab)
“Feces were collected predose on day 1 and postdose on day 8 between 0 and 12 hours.” (opens the source at this quote in a new tab)
“Thereafter, feces collection intervals were the same as for urine.” (opens the source at this quote in a new tab)
“Metabolite profiling was done using pooled urine samples (0-192 hours) and pooled feces samples (24-240 hours).” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: open-label, single-center, single-dose design with two radiolabel positions

“Trial 2. This was an open label, single-center trial to investigate the mass balance and metabolite profile of pritelivir after a single dose in healthy male subjects.” (opens the source at this quote in a new tab)
“On day 1, 6 subjects received a single oral 100 mg dose of pritelivir spiked with 14C-pritelivir, labeled at the pyridinyl phenyl acetic moiety, and 14C-pritelivir, labeled at the amino thiazole sulfonamide moiety (Figure 1).” (opens the source at this quote in a new tab)
“The amount of 14C-pritelivir, labeled at each of the 2 moieties, did not exceed 50 kBq each and not more than 100 kBq (2.7 μCi) in total.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: reason for labeling both moieties

“Because in the first trial pritelivir was labeled at only 1 position in the molecule, some metabolites remained undetectable.” (opens the source at this quote in a new tab)
“Therefore, in the second trial, pritelivir was dosed as an equimolar mixture of the molecules with the 14C label either on one or on the other side.” (opens the source at this quote in a new tab)
“Thus, where the molecular structure was split into 2 parts, the radiolabels were equally divided over both sides of the molecule.” (opens the source at this quote in a new tab)
“For the comparison of TRA measurements, the number of labels for each molecule was taken into account.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: screening, confinement, and follow-up

“For each subject, the screening examination took place within 21 days before trial mediation.” (opens the source at this quote in a new tab)
“Subjects were hospitalized from day 1 to day 27 and returned to the clinic for a follow-up visit between days 30 and 37 (Figure 2).” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: blood sampling schedule

“Blood samples for PK analysis of pritelivir and metabolites PPA, aminothiazole sulfonamide (ATS) and PPA-acyl glucuronide in plasma and blood (3 mL at each time point per matrix) were collected predose on day 1 and postdose at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48, 60, 72, 96, 120, 144, 168, 192, 216, 240, 288, 336, 384, 432, 480, 528, 576, and 624 hours.” (opens the source at this quote in a new tab)
“Blood samples for PK analysis of TRA in plasma and blood (4 mL for plasma and 2 mL for blood) were collected predose on day 1 and postdose at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48, 60, 72, 96, 120, 144, 168, 192, 216, 240, 288, 336, 384, 432, 480, 528, 576, and 624 hours.” (opens the source at this quote in a new tab)
“Additional blood samples of 4 mL were collected for metabolite profiling on day 1 postdose at 2, 4, 24, 480, and 624 hours.” (opens the source at this quote in a new tab)
“Metabolite profiling was done using pooled plasma samples (0-336 hours).” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: urine and feces collection schedule

“Urine was collected on day 1 between 0-4, 4-8, 8-12, 12-24, 48-96, 96-144, 144-192, 192-240, 240-288, 288-336, 336-384, 384-432, 432-480, 480-528, 528-576, and 576-624 hours.” (opens the source at this quote in a new tab)
“Metabolite profiling was done using pooled urine samples (0-432 hours) and pooled feces samples (0-384 hours).” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: bioanalytical methods and lower limits of quantification

“All analyses were undertaken using fully validated procedures.” (opens the source at this quote in a new tab)
“The lower limit of quantification (LLOQ) for the assay of pritelivir in plasma was 2.00 ng/mL.” (opens the source at this quote in a new tab)
“TRA and concentrations of 14C labeled pritelivir and its metabolites in plasma, urine, and feces were determined using AMS and HPLC-AMS by Xceleron Ltd, (York, United Kingdom).” (opens the source at this quote in a new tab)
“The LLOQ for TRA was 0.3254-0.6471 pg equiv. in plasma, 0.0024-0.0376 dpm/mL in urine, and 0.8439-1.8888 dpm/g in feces.” (opens the source at this quote in a new tab)
“Metabolites were structurally identified by HPLC-MS and HPLC-MS/MS.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: bioanalytical methods and lower limits of quantification

“Plasma and whole-blood concentrations of pritelivir were determined using a validated mass spectrometry, liquid chromatography method (HPLC-MS/MS) by A&M Labor für Analytik und Metabolismusforschung Service GmbH (Bergheim, Germany).” (opens the source at this quote in a new tab)
“The LLOQs for pritelivir, PPA, ATS, and PPA-acyl glucuronide in plasma and whole blood were 10.00, 2.00, 2.00, and 0.1 (plasma only) ng/mL, respectively.” (opens the source at this quote in a new tab)
“TRA in plasma, urine, and feces, was determined using AMS by TNO (Leiden, The Netherlands).” (opens the source at this quote in a new tab)
“The LLOQs for TRA were 1.65, 5.78, and 1.18 ng/eq/mL and 3.04 ng/eq/g in plasma, whole blood, urine, and feces, respectively.” (opens the source at this quote in a new tab)
“Metabolite identification was performed by TNO.” (opens the source at this quote in a new tab)

Inclusion criteria: healthy men, with age and body mass index limits by trial

“Healthy male subjects of any ethnic origin, aged between 18 and 45 years inclusive (Trial 1) or aged between 18 and 55 years inclusive (Trial 2), with a body mass index between ≥18.0 and ≤28.0 kg/m2 (Trial 1) or between ≥18.0 and ≤30.0 kg/m2 (Trial 2), and a body weight of >50 kg were eligible for enrollment.” (opens the source at this quote in a new tab)
“All subjects were assessed as healthy based on a pre-trial examination including medical history, physical examination, blood pressure, pulse rate, electrocardiogram (ECG) assessment, and clinical laboratory results.” (opens the source at this quote in a new tab)

Exclusion criteria in both trials: disease history and abnormal findings

“Subjects with a history or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematological, endocrinological, metabolic, neurological, psychiatric, or other disease or malignancy were excluded.” (opens the source at this quote in a new tab)
“Subjects were also excluded in case of any clinically relevant abnormalities in ECG, vital signs, clinical chemistry, hematological, or any other laboratory values.” (opens the source at this quote in a new tab)

Prior and concomitant medication restrictions in both trials

“Subjects were not allowed to use any medication (including over-the-counter medication) within 2 weeks or within less than 10 times the elimination half-life of the respective drug before trial drug administration.” (opens the source at this quote in a new tab)
“Treatment with any agent known to induce or inhibit metabolizing enzymes or transporters was not allowed within 2 weeks prior to the trials.” (opens the source at this quote in a new tab)
“Concomitant medications were generally not allowed throughout the trial except for paracetamol on demand.” (opens the source at this quote in a new tab)

Diet, smoking, and alcohol restrictions in both trials

“Subjects were not allowed to consume any enzyme-inducing or -inhibiting food and beverages within 2 weeks prior to the start of the trial and no enzyme activity influencing fluids or beverages were allowed during the in-house period.” (opens the source at this quote in a new tab)
“Consumption of any methylxanthine-containing product was not allowed within 48 hours prior to administration of the investigational medicinal product until discharge.” (opens the source at this quote in a new tab)
“Subjects were excluded when smoking more than 5 cigarettes per day.” (opens the source at this quote in a new tab)
“Subjects were not allowed to smoke or consume alcohol within 2 days prior to administration until discharge.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: pritelivir 500 mg on day 1, then 100 mg daily, with a radiolabeled microdose on day 8

“Eight subjects received a single oral dose of 500 mg pritelivir on day 1, followed by 7 daily oral doses of 100 mg (days 2-8).” (opens the source at this quote in a new tab)
“On day 8 the oral dose was spiked with 3 μg (9.3 kBq) of 14C-pritelivir, labeled at the pyridinyl phenyl acetic moiety (Figure 1).” (opens the source at this quote in a new tab)
“Subjects fasted overnight from 10 pm on the evening of day 7 until 4 hours after dosing on day 8.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: single 100 mg dose of pritelivir with two radiolabeled tracers

“On day 1, 6 subjects received a single oral 100 mg dose of pritelivir spiked with 14C-pritelivir, labeled at the pyridinyl phenyl acetic moiety, and 14C-pritelivir, labeled at the amino thiazole sulfonamide moiety (Figure 1).” (opens the source at this quote in a new tab)
“The amount of 14C-pritelivir, labeled at each of the 2 moieties, did not exceed 50 kBq each and not more than 100 kBq (2.7 μCi) in total.” (opens the source at this quote in a new tab)
“Subjects fasted overnight from 10 hours before until 4 hours after dosing.” (opens the source at this quote in a new tab)

Formulations used in each trial

“One of the main differences between Trial 1 and Trial 2 was the trial medication.” (opens the source at this quote in a new tab)
“In Trial 1 unlabeled pritelivir was dosed as the clinical tablet formulation, and the labeled pritelivir was dosed in a gelatine capsule.” (opens the source at this quote in a new tab)
“In contrast, in Trial 2, unlabeled pritelivir was dosed as unformulated active pharmaceutical ingredient (API) in an hydroxypropyl methylcellulose (HPMC) capsule.” (opens the source at this quote in a new tab)
“An ethanolic solution of the microtracers was spiked on the API surface contained in the HPMC capsule.” (opens the source at this quote in a new tab)

Radiolabeled microdose measured by accelerator mass spectrometry

“Accelerator mass spectrometry (AMS) is a very sensitive method to detect trace amounts of 14C.” (opens the source at this quote in a new tab)
“With this technique, it is possible to accurately measure the amount of 14C in biological samples after administration of a relatively small dose of 14C (about ∼10 or 20 kBq)” (opens the source at this quote in a new tab)
“thus limiting the exposure of the trial participants to radioactive radiation (previously in the 1-3 MBq range).” (opens the source at this quote in a new tab)

Excretion of total radioactivity as a percentage of the administered dose

“Urine and feces were collected to determine the recovery of TRA and for the identification of metabolites.” (opens the source at this quote in a new tab)
“For TRA in urine, feces and total excreta (urine and feces combined), the cumulative amount of TRA as a function of time in urine (Aeurine), feces (Aefeces), and total (Aetotal) was calculated for each subject and expressed as the percentage of dose administered.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: plasma pharmacokinetic parameters calculated

“Trial 1. For pritelivir and TRA (dose-normalized to 100 mg) in plasma.” (opens the source at this quote in a new tab)
“On days 2-8: C0h (pritelivir only); on day 8: Cmin, Cmax (TRA only), Cmax,ss (pritelivir only), tmax, AUCτ,ss, AUC0-24, AUC0-last, AUC0-inf, t1/2z, CL/F (pritelivir only) and Vss/F (pritelivir only).” (opens the source at this quote in a new tab)
“In addition, the ratio of AUCτ,ss of pritelivir over AUC0-last and AUC0-inf of TRA in plasma was calculated.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: plasma and whole-blood pharmacokinetic parameters calculated

“Trial 2. For pritelivir, metabolites and TRA (dose-normalized to 100 mg) in plasma and whole blood (PPA-acyl glucuronide in plasma only): Cmax, tmax, tlag, AUC0-last, AUC0-inf, t1/2z, CL/F (pritelivir only) and Vss/F (pritelivir only).” (opens the source at this quote in a new tab)
“In addition, blood to plasma (BP) ratios were determined for Cmax, AUC0-last, AUC0-inf and concentration per timepoint.” (opens the source at this quote in a new tab)

Safety and tolerability assessments in both trials

“Safety assessments in both trials consisted of adverse events (AEs) monitoring, vital signs, ECG, physical examination, and laboratory tests.” (opens the source at this quote in a new tab)
“All AEs were coded according to the MedDRA (version 13.1 for AIC316-01-I-04 and version 24.1 for AIC316-03-I-02).” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: participants enrolled and analyzed

“In total 8 healthy male subjects were enrolled in the trial.” (opens the source at this quote in a new tab)
“All subjects received the trial medication as planned and were included in the safety and PK population.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: participants contributing to each parameter

Analyte or measure	Participants contributing
Pritelivir in plasma	“n = 7 for AUC0-last, AUC0-inf and t1/2z.”
Total radioactivity in plasma	“n = 7 for AUC0-last, n = 3 for AUC0-inf and t1/2z.”
Recovery of total radioactivity in excreta	“Trial 1 0-624 hours (n = 7)”

Trial AIC316-03-I-02: participants enrolled and analyzed

“In total 6 healthy male subjects were enrolled in the trial.” (opens the source at this quote in a new tab)
“All subjects completed the trial and were included in the safety and PK population.” (opens the source at this quote in a new tab)

Safety and pharmacokinetic population in both trials

“All subjects received the trial medication as planned and were included in the safety and PK population.” (opens the source at this quote in a new tab)
“All subjects completed the trial and were included in the safety and PK population.” (opens the source at this quote in a new tab)

Noncompartmental analysis and descriptive statistics

“For both trials PK analyses were performed with standard noncompartmental methods using the validated computer program Phoenix WinNonlin (version 4.1 and 8.1; Certara USA Inc., Princeton, New Jersey).” (opens the source at this quote in a new tab)
“PK parameters for pritelivir (free base) and metabolites (PPA, ATS, and PPA-acyl glucuronide) were calculated based on the individual plasma, whole-blood, urine, and feces concentration versus time data using the actual sampling and times and collection intervals.” (opens the source at this quote in a new tab)
“Descriptive statistics were calculated for the PK parameters of pritelivir and included sample size (n), mean, standard deviation (SD), coefficient of variation (% CV), geometric mean, median, minimum, and maximum.” (opens the source at this quote in a new tab)

Safety analysis by descriptive statistics

“The results of these safety measurements and AEs were listed by subject and treatment group, and analyzed by descriptive statistics.” (opens the source at this quote in a new tab)
“Incidences of treatment-emergent adverse events (TEAEs; beginning after the start of treatment) were summarized by the overall subjects’ level (occurrence of at least 1 TEAE), primary system organ class (SOC) level, and preferred term (Pt) level.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: one of 8 participants withdrew after the last dose

“In total 8 healthy male subjects were enrolled in the trial.” (opens the source at this quote in a new tab)
“One subject suffered headache and migraine on day 13 (5 days after last dose), and withdrew from the trial.” (opens the source at this quote in a new tab)
“This subject did not complete the blood, urine and fecal collections between days 14 and 34.” (opens the source at this quote in a new tab)
“Unscheduled fecal and blood samples were collected from the subject at follow-up.” (opens the source at this quote in a new tab)
“The subject was not replaced.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: all 6 participants completed

“In total 6 healthy male subjects were enrolled in the trial.” (opens the source at this quote in a new tab)
“All subjects completed the trial and were included in the safety and PK population.” (opens the source at this quote in a new tab)

Sex and health status of the enrolled participants in both trials

“In total 8 healthy male subjects were enrolled in the trial.” (opens the source at this quote in a new tab)
“In total 6 healthy male subjects were enrolled in the trial.” (opens the source at this quote in a new tab)

Demographics reported in a supplementary table

“The demographics of the safety population for each trial are summarized in Table S1.” (opens the source at this quote in a new tab)

Recovery of total radioactivity in urine and feces over 0 to 624 hours in both trials

Amount excreted, mean (mean % of recovered dose)	Trial AIC316-01-I-04 (n = 7)	Trial AIC316-03-I-02 (n = 6)
Urine (% of dose)	“76.4 (83.0)”	“50.8 (76.9)”
Feces (% of dose)	“15.5 (16.8)”	“15.2 (23.0)”
Total (% of dose)	“92.0 (100)”	“66.0 (100)”

Trial AIC316-01-I-04: recovery of the administered radioactive dose

“Radioactivity was detected in all urine and fecal collections, up to the final interval.” (opens the source at this quote in a new tab)
“The mean percentage of the administered radioactive dose recovered was 92.0% (range 70.4%-108%), with 76.4% recovered in urine and 15.5% recovered in feces (Table 2 and Figure 4).” (opens the source at this quote in a new tab)
“Individual recovery ranged from 53.9% to 95.0% in urine and from 10.8% to 21.8% in feces.” (opens the source at this quote in a new tab)
“Intersubject variability (%CV) for recovery in urine and feces was 18% and 24%, respectively.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: recovery of the administered radioactive dose

“Radioactivity was detected in all urine collections and almost all feces collections, up to the final interval.” (opens the source at this quote in a new tab)
“In total, 66% of the administered radioactive dose was recovered in excreta (range 53.1%-76.3%), with 50.8% (range 30.6%-65.7%) and 15.2% (range 2.3%-33.1%) recovered in urine and feces, respectively.” (opens the source at this quote in a new tab)
“This corresponds to 77.0% and 23.0% relative to the 66% of radioactive dose recovered for urine and feces, respectively (Table 2 and Figure 4), which is comparable to the recovery in excreta observed in Trial 1.” (opens the source at this quote in a new tab)
“Intersubject variability (%CV) for recovery in urine and feces was 25% and 73%, respectively.” (opens the source at this quote in a new tab)
“As detailed in the Discussion section, the lower recovery compared to Trial 1 (66% vs 92%) could be attributed to an incomplete absorption of the pritelivir dose in Trial 2.” (opens the source at this quote in a new tab)

Recovery, excretion route, and plasma composition as summarized in the abstract

“The plasma half-life of pritelivir was 63-67 hours.” (opens the source at this quote in a new tab)
“Overall, 92% and 66% of the administered dose was recovered in the multiple and single dose trials, respectively.” (opens the source at this quote in a new tab)
“More than 90% of drug-related material was eliminated 624 hours postdose.” (opens the source at this quote in a new tab)
“The majority was excreted in urine (75% and 77%), followed by feces (16% and 23%).” (opens the source at this quote in a new tab)
“In plasma, pritelivir, ATS, PPA, and PPA-acyl glucuronide accounted for 40.6%, 9.4%, 5.1%, and 0.2% of total radioactivity.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: plasma pharmacokinetics of pritelivir and total radioactivity

“After multiple oral doses of unlabeled pritelivir (days 1-8) and a single oral dose of 14C-labeled pritelivir (day 8), pritelivir and TRA were rapidly absorbed.” (opens the source at this quote in a new tab)
“Mean plasma concentrations of both pritelivir and TRA peaked at 4 hours after dosing (Figure 3).” (opens the source at this quote in a new tab)
“There was a second increase in mean plasma concentration between 8 and 10 hours after administration for pritelivir and between 5 and 10 hours for TRA.” (opens the source at this quote in a new tab)
“Median tmax was at 3 and 4 hours for pritelivir and TRA, respectively, postdose on day 8.” (opens the source at this quote in a new tab)
“Mean concentrations of pritelivir and TRA declined in parallel up to 336 hours, thereafter a second elimination phase was observed for TRA up to 624 hours postdose.” (opens the source at this quote in a new tab)
“The mean t1/2z for pritelivir was 63 hours and about 228 hours for TRA, although for the latter t1/2z could not be determined accurately (Table 1).” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: share of plasma radioactivity accounted for by pritelivir

“The mean Cmax,ss of pritelivir on day 8 was about 1.8 times the Cmax equivalent for TRA (Table 1), as pritelivir was at steady state on day 8, whereas 14C-labeled pritelivir had been administered as a single dose.” (opens the source at this quote in a new tab)
“The geometric mean ratio of AUCτ,ss (pritelivir) to AUC0-inf (TRA) was 45.2%, suggesting that 45.2% of the TRA could be accounted for by the parent drug and the remainder could be attributable to metabolites.” (opens the source at this quote in a new tab)
“A similar result (47.9%) was obtained when considering AUC0-last as a suitable approximation for AUC0-inf as AUC0-inf could not be determined reliably (%AUCex was high).” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: pharmacokinetic parameters of pritelivir and dose-normalized total radioactivity

Parameter, mean (SD); tmax, median (range)	Pritelivir (n = 8)	Total radioactivity (n = 8)
C0h (ng/mL), day 2	“5222 (2731)”	“N.A.”
C0h (ng/mL), day 3	“5289 (1426)”	“N.A.”
C0h (ng/mL), day 4	“4259 (1050)”	“N.A.”
C0h (ng/mL), day 5	“3964 (956.1)”	“N.A.”
C0h (ng/mL), day 6	“3944 (990.6)”	“N.A.”
C0h (ng/mL), day 7	“4017 (984.0)”	“N.A.”
C0h (ng/mL), day 8	“3458 (772.9)”	“N.A.”
Cmin (ng/mL)	“3194 (739.1)”	“N.A.”
Cmax ([ng eq]/mL)	“N.A.”	“3356 (1832)”
Cmax,ss (ng/mL)	“5889 (1924)”	“N.A.”
tmax (h)	“3.00 (0.75-5.00)”	“4.00 (0.50-10.10)”
AUCtau (ng/h/mL)	“102,941 (25170)”	“N.A.”
AUC0-24 ([ng eq]/h/mL)	“N.A.”	“57,167 (20,966)”
AUC0-last (ng [eq]/h/mL)	“301,124 (57,966)”	“199,871 (18,884)”
AUC0-inf (ng [eq]/h/mL)	“306,430 (58,580)”	“197,211 (18,004)”
t1/2z (h)	“63.06 (1.904)”	“227.8 (5.704)”
CL/F (L/h)	“1.022 (0.2434)”	“N.A.”

Trial AIC316-01-I-04: notes to the pharmacokinetic parameter table

Note applies to	Note as printed
Total radioactivity	“Scaled to a 100 mg dose.”
Units of AUC0-last and AUC0-inf	“Units are ng/h/mL for pritelivir and [ng eq]/h/mL for 14C labeled pritelivir.”
AUC0-inf and t1/2z of total radioactivity	“Accurate determination is not possible.”

Trial AIC316-03-I-02: plasma and whole-blood pharmacokinetics of pritelivir and total radioactivity

“After a single oral dose of unlabeled and 14C-labeled pritelivir, TRA was more rapidly absorbed compared to pritelivir.” (opens the source at this quote in a new tab)
“Mean plasma and whole-blood concentrations of both pritelivir and TRA peaked at 4 and 10 hours after dosing (Figure 5).” (opens the source at this quote in a new tab)
“Median tmax was at 7 and 7.5 hours for pritelivir and at 4 and 0.9 hours for TRA in plasma and whole blood, respectively.” (opens the source at this quote in a new tab)
“Mean concentrations of pritelivir and TRA declined more or less in parallel up to 336 hours, after which TRA appeared to decline at a slower rate, although samples could not be measured for pritelivir beyond 336 hours (below LLOQ).” (opens the source at this quote in a new tab)
“In plasma, the mean t1/2z values were 67.1 and 119 hours and in whole blood they were 76.5 and 95.6 hours for pritelivir and TRA, respectively (Table 3).” (opens the source at this quote in a new tab)
“The mean Cmax for TRA in plasma and whole blood was approximately 1.9- and 1.6-fold higher, respectively, compared to pritelivir, while for mean AUC0-last and AUC0-inf, TRA was approximately 2.4-fold higher in both plasma and whole blood.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: share of total radioactivity by analyte in plasma and whole blood

“Pritelivir accounted for the highest percentage of TRA (40.6%) in plasma, followed by the metabolites PPA (9.4%), ATS (5.1%), and PPA-acyl glucuronide (0.2%), based on the geometric mean.” (opens the source at this quote in a new tab)
“In whole blood, pritelivir also accounted for the highest percentage of TRA (38.8%), followed by ATS (18.2%) and PPA (1.1%) (Table 3).” (opens the source at this quote in a new tab)
“PPA-acyl glucuronide was not measured in whole blood.” (opens the source at this quote in a new tab)
“Metabolite over parent ratios in plasma, based on AUC0-inf and corrected for molecular weight in order from high to low were 0.442 (PPA), 0.247 (ATS), and 0.00544 (PPA-acyl glucuronide) and for whole blood were 0.920 (ATS) and 0.0544 (PPA) (Table 3).” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: whole-blood to plasma ratios

“Mean whole-blood to plasma ratios were high for TRA (4.91), pritelivir (4.69), and ATS (17.32) and low for PPA (0.58).” (opens the source at this quote in a new tab)
“The whole-blood to plasma ratios were generally consistent across the concentration-time profiles for pritelivir, PPA, and ATS (Figure 6).” (opens the source at this quote in a new tab)
“For TRA, the whole blood to plasma ratios appeared to be dependent on TRA plasma concentrations and ranged between 3.9 and 6.6.” (opens the source at this quote in a new tab)

Blood to plasma ratio, mean (SD)	Pritelivir	PPA	ATS	Total radioactivity
Based on AUC0-last	“4.82 (0.78)”	“0.57 (0.05)”	“18.40 (2.44)”	“4.94 (0.84)”
Based on AUC0-inf	“4.69 (0.74)”	“0.58 (0.04)”	“17.32 (2.23)”	“4.91 (0.84)”
Based on Cmax	“4.36 (1.00)”	“0.62 (0.07)”	“16.16 (2.68)”	“3.81 (1.35)”

Trial AIC316-03-I-02: plasma pharmacokinetic parameters of pritelivir, metabolites, and total radioactivity

Parameter, mean (SD); tmax and tlast, median (range)	Pritelivir (n = 6)	PPA (n = 6)	ATS (n = 6)	PPA-acyl glucuronide (n = 6)	Total radioactivity (n = 6)
Cmax (ng [eq]/mL)	“667 (335)”	“115 (57.1)”	“39.1 (17.0)”	“2.94 (1.90)”	“1282 (438)”
tmax (h)	“7 (4-10)”	“24 (24-24)”	“66.03 (60-96)”	“10 (10-24)”	“4 (0.75-10)”
Clast (ng [eq]/mL)	“13.1 (2.20)”	“2.56 (0.303)”	“2.70 (0.373)”	“0.114 (0.0103)”	“11.9 (0.691)”
tlast (h)	“336 (288-336)”	“336 (336-432)”	“360 (336-432)”	“288 (216-336)”	“624 (624-624)”
AUC0-last (ng[eq]/h/mL)	“47,038 (17,417)”	“11,138 (4571)”	“5741 (1926)”	“250 (124)”	“111,200 (21,720)”
AUC0-inf (ng[eq]/h/mL)	“48,313 (17,250)”	“11,392 (4503)”	“6059 (1874)”	“261 (122)”	“113,249 (21,697)”
t1/2z (h)	“67.1 (13.1)”	“69.1 (17.4)”	“81.8 (20.0)”	“68.4 (14.9)”	“119 (4.5)”

Trial AIC316-03-I-02: whole-blood pharmacokinetic parameters of pritelivir, metabolites, and total radioactivity

Parameter, mean (SD); tmax and tlast, median (range)	Pritelivir (n = 6)	PPA (n = 6)	ATS (n = 6)	Total radioactivity (n = 6)
Cmax (ng [eq]/mL)	“2830 (1489)”	“72.6 (37.8)”	“609 (238)”	“4505 (974)”
tmax (h)	“7.51 (4-24)”	“24 (10-24)”	“60 (48-72)”	“0.88 (0.75-10)”
Clast (ng [eq]/mL)	“11.9 (1.29)”	“2.37 (0.268)”	“6.42 (5.28)”	“45.9 (16.7)”
tlast (h)	“504 (432-624)”	“288 (240-384)”	“624 (576-624)”	“624 (624-624)”
AUC0-last (ng[eq]/h/mL)	“225,229 (86,963)”	“6444 (2779)”	“104,432 (35,744)”	“538,154 (70,754)”
AUC0-inf (ng[eq]/h/mL)	“226,534 (86,827)”	“6688 (2685)”	“105,241 (36,052)”	“544,617 (71,238)”
t1/2z (h)	“76.5 (13.4)”	“70.3 (23.7)”	“80.3 (15.3)”	“95.6 (7.4)”

Trial AIC316-03-I-02: apparent clearance of pritelivir

Matrix	CL/F (L/h), mean (SD)
Plasma	“2.45 (1.23)”
Whole blood	“0.536 (0.293)”

Trial AIC316-01-I-04: metabolite identification in plasma

“A pool sample was prepared from individual plasma samples collected between 0 and 24 hours postdose on day 8.” (opens the source at this quote in a new tab)
“Overall, 72.5% of the TRA present was associated with pritelivir, while 24.4% was associated with PPA.” (opens the source at this quote in a new tab)
“Furthermore, small amounts of hydroxylated pritelivir and ATS were identified by HPLC-MS/MS in the plasma pool.” (opens the source at this quote in a new tab)
“ATS was not detected in the HPLC-AMS analysis as it lacked the 14C label at the ATS moiety.” (opens the source at this quote in a new tab)
“The extraction efficiency of radioactivity from pooled plasma samples was about 77%.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: metabolite identification in urine

“In pooled urine collected between 0 and 192 hours postdose on day 8, the major region accounted for 62.0% of TRA present (42.2% of the administered dose) and was identified as PPA-acyl glucuronide.” (opens the source at this quote in a new tab)
“PPA and several isomers of the PPA-acyl glucuronide accounted for 17.3% (11.8% of the administered dose).” (opens the source at this quote in a new tab)
“Pritelivir accounted for 0.9% (0.6% of the administered dose).” (opens the source at this quote in a new tab)
“In addition, 3 metabolites accounting for 2.0%-5.0% of the TRA present (1.4%-3.4% of the administered dose) were not identified.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: metabolite identification in feces

“In pooled feces collected between 24 and 240 hours postdose on day 8, the major region was identified as parent compound accounting for 43.1% of the TRA present (6.0% of the administered dose).” (opens the source at this quote in a new tab)
“Hydroxylated pritelivir accounted for 14.0% of the TRA present (1.9% of the administered dose).” (opens the source at this quote in a new tab)
“In addition, there were 6 metabolites accounting for 16.8% and 1.7%-5.4% of TRA present (2.3% and 0.2%-0.7% of the administered dose) which could not be identified.” (opens the source at this quote in a new tab)
“Note that due to low extraction efficiency (37.4%) for the feces sample, the reported percentages of pritelivir and metabolites in feces may not fully reflect the absolute proportions of these compounds.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: metabolite identification in plasma

“In pooled plasma samples collected between 0 and 336 hours, 3 main peaks were identified as pritelivir, PPA, and ATS, which accounted for 58.3%, 10.1%, and 5.9%, respectively, of TRA present.” (opens the source at this quote in a new tab)
“One additional peak accounting for 1.9% of TRA was tentatively assigned as hydroxylated pritelivir (aliphatic hydroxylation).” (opens the source at this quote in a new tab)
“The remainder (23.8%) was exposure to other 14C-labeled material, which did not show as clear peaks and could not be identified (see Figure S2 and Table S4).” (opens the source at this quote in a new tab)
“The extraction efficiency of radioactivity from pooled plasma samples was 99.9%.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: metabolite identification in urine

“In pooled urine collected between 0 and 432 hours postdose, a total of 12 pritelivir-related peaks were detected.” (opens the source at this quote in a new tab)
“The main component in urine was identified as PPA-β-1-acyl glucuronide, accounting for 29.6% of TRA present (44.5% of the recovered dose).” (opens the source at this quote in a new tab)
“Three isomers of PPA-acyl glucuronide accounting for 2.0%-3.4% were also detected (3.0%-5.1% of the recovered dose).” (opens the source at this quote in a new tab)
“In total, PPA-acyl glucuronide and isomers accounted for 38.2% of the TRA in urine (57% of the recovered dose).” (opens the source at this quote in a new tab)
“ATS accounted for 23.1% of TRA (34.7% of the recovered dose).” (opens the source at this quote in a new tab)
“An additional metabolite was tentatively identified as N-demethylated ATS, accounting for 12.8% of the TRA (19.2% of the recovered dose).” (opens the source at this quote in a new tab)
“PPA accounted for 2.1%, hydroxylated pritelivir accounted for 1.9%, and pritelivir accounted for 0.6% (3.2%, 1.4%, and 0.5% of the recovered dose, respectively).” (opens the source at this quote in a new tab)
“Four minor metabolites were tentatively assigned to N-demethylated ATS (2.0%), hydroxylated and glucuronidated pritelivir (1.1%), glucuronidated pritelivir (2.1%), and hydroxylated PPA (1.5%).” (opens the source at this quote in a new tab)
“In urine, 84.9% of TRA was assigned to peaks with relative abundances above 1%.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: metabolite identification in feces

“In pooled feces homogenate collected between 0 and 384 hours postdose, 1 major and 3 minor peaks (with relative abundances above 1%) were observed.” (opens the source at this quote in a new tab)
“The main peak corresponded to the parent drug, which accounted for 70.6% of TRA (16.0% of the recovered dose).” (opens the source at this quote in a new tab)
“Additionally, 2 peaks both accounting for 1.3% of TRA (0.6% of the recovered dose) were assigned to N-demethylated ATS.” (opens the source at this quote in a new tab)
“Hydroxylated pritelivir was assigned to peaks accounting for TRA of 6.4% (1.5% of the recovered dose).” (opens the source at this quote in a new tab)
“In feces, 79.7% of TRA was assigned to peaks (above 1%).” (opens the source at this quote in a new tab)
“The extraction efficiency of radioactivity from pooled feces samples was 121.5%.” (opens the source at this quote in a new tab)

Urinary PPA-acyl glucuronide compared between the trials

“In Trial 2, PPA-acyl glucuronide accounted for 29.4% of the administered dose in urine, which was lower compared to Trial 1 (42.2%) due to the incomplete recovery.” (opens the source at this quote in a new tab)
“However, when adjusting for the incomplete recovery, the excretion was 44.5% of the recovered dose in line with Trial 1.” (opens the source at this quote in a new tab)
“In Trial 1, pritelivir accounted for 6% of the administered dose in feces, which was higher in Trial 2 (16.0% of the recovered dose) most likely due to the incomplete absorption.” (opens the source at this quote in a new tab)

Metabolic pathways proposed from both trials

“The major metabolic pathway was amide hydrolysis leading to amino thiazole sulfonamide (ATS) and pyridinyl phenyl acetic acid (PPA).” (opens the source at this quote in a new tab)
“These results suggest that pritelivir was mainly cleared by amide hydrolysis, resulting in 2 cleavage products: PPA (the carboxylic acid derivative of pritelivir), which subsequently conjugated to form PPA-glucuronide and corresponding isomers or further hydroxylated, and ATS (the thiazole sulfonamide derivative of pritelivir), which was subsequently N-demethylated.” (opens the source at this quote in a new tab)
“Aliphatic hydroxylation (hydroxylated pritelivir) is a minor elimination pathway as well as glucuronidation and hydroxylation of pritelivir (hydroxylated and glucuronidized pritelivir and pritelivir-glucuronide).” (opens the source at this quote in a new tab)
“In human microsomes, the major metabolite was formed by aliphatic hydroxylation, which was mediated by CYP3A4, although this was identified to be a minor elimination pathway in the human mass balance studies.” (opens the source at this quote in a new tab)

Distribution into red blood cells

“High blood to plasma ratios were observed for AUC0-inf of TRA (4.91), pritelivir (4.69), and ATS (17.32), indicating substantial drug distribution into the red blood cells.” (opens the source at this quote in a new tab)
“This can probably be explained by non-covalent binding of pritelivir to CA, present in red blood cells.” (opens the source at this quote in a new tab)
“As a result, the blood to plasma ratio for pritelivir and ATS, but not PPA, is higher than 1.” (opens the source at this quote in a new tab)
“The low blood/plasma ratio for PPA (0.58) suggests that there is no distribution into red blood cells.” (opens the source at this quote in a new tab)

Authors' conclusions from both trials

“In conclusion, the overall recovery of 92% within 624 hours after dose administration with the main elimination route being renal as determined in Trial 1 is deemed adequate to describe the overall elimination time course of drug-related material.” (opens the source at this quote in a new tab)
“Pritelivir was the main component in plasma, representing 41%-48% of the TRA.” (opens the source at this quote in a new tab)
“PPA, ATS, and PPA-acyl glucuronide represented 9.4%, 5.1%, and 0.2% of the TRA in plasma, respectively.” (opens the source at this quote in a new tab)
“The acyl glucuronide of PPA and its isomers next to ATS and its N-demethylated isomers were the main metabolites in the urine.” (opens the source at this quote in a new tab)
“In feces, pritelivir (representing most likely unabsorbed pritelivir) and its hydroxylated form were the main components.” (opens the source at this quote in a new tab)
“In conclusion, these 2 human mass balance trials showed that pritelivir was largely metabolized, with the primary route of excretion being renal.” (opens the source at this quote in a new tab)
“Based on the assigned metabolites, pritelivir underwent mainly amide hydrolysis and (further) glucuronidation and N-demethylation.” (opens the source at this quote in a new tab)

Prescribing information: metabolism and excretion of pritelivir

Property	Value as printed
Metabolism	“Pritelivir is primarily metabolized by non-enzymatic hydrolysis to its major inactive metabolites,”
Metabolite AIC090015, molar ratio to total drug-related material in plasma	“AIC090015 (26.3%)”
Metabolite AIC090105, molar ratio to total drug-related material in plasma	“AIC090105 (14.4%)”
Dose excreted in urine	“76.4% (0.6% unchanged)”
Dose excreted in feces	“15.5% (6.0% unchanged)”
Major route of elimination	“Non-enzymatic hydrolysis, followed by urinary excretion of the metabolites”
Blood-to-plasma ratio, mean	“AUC: 1.86”
Half-life, mean	“60 h”

Prescribing information: mass balance study described in the table notes

“Percentages represent the molar ratio of each metabolite to total drug-related material in plasma.” (opens the prescribing information at this quote)
“Dosing in mass balance study: Healthy participants received pritelivir 500 mg (loading dose, Day 1) and 100 mg once daily (Days 2-8), with a [14C]-labeled tracer dose co-administered on Day 8.” (opens the prescribing information at this quote)
“Values represent recovery of total radioactivity as a percentage of administered dose.” (opens the prescribing information at this quote)

Trial AIC316-01-I-04: treatment-emergent adverse events

“The administration of pritelivir (days 1-8) and 14C-labeled pritelivir (day 8) was generally well tolerated.” (opens the source at this quote in a new tab)
“Four out of 8 subjects experienced a total of 7 TEAEs.” (opens the source at this quote in a new tab)
“Nervous system events were most common (5 events in 3 subjects).” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: headache, migraine, and withdrawal

“One subject experienced a moderate headache starting 5 days after the last trial medication which developed into migraine within a few hours.” (opens the source at this quote in a new tab)
“The migraine led to withdrawal of the subject.” (opens the source at this quote in a new tab)
“Another subject experienced a moderate headache on day 10 (2 days after the last trial medication).” (opens the source at this quote in a new tab)
“The other nervous system events were mild.” (opens the source at this quote in a new tab)
“All the nervous system events lasted for no longer than 24 hours and were considered to be possibly related to the trial treatment by the investigator.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: events considered unlikely to be related

“The remaining 2 adverse events were mild, occurred at more than 10 days after the last trial medication, and were considered unlikely to be related to the trial treatment by the investigator.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: treatment-emergent adverse events

“The administration of a single dose of pritelivir and 14C-labeled pritelivir was generally well tolerated.” (opens the source at this quote in a new tab)
“Two out of 6 subjects experienced a total of 12 TEAEs.” (opens the source at this quote in a new tab)
“All events were of mild intensity and were reported recovered at the end of the trial.” (opens the source at this quote in a new tab)
“One subject experienced 3 events (diarrhea, dry mouth, and headache) on day 1 of the trial that were considered to be possibly related to the trial treatment by the investigator.” (opens the source at this quote in a new tab)

Summary

The trials enrolled 8 and 6 healthy men in open-label, single-center designs. In the single-dose trial, 66.0% of the radioactive dose was recovered, which the authors attribute to slow capsule dissolution and incomplete absorption; plasma exposure was about 2-fold lower than in previous trials. In the multiple-dose trial, the single label position left some metabolites undetectable, fecal extraction efficiency was 37.4%, one participant withdrew before collections ended, and AUC0-inf of total radioactivity could not be determined accurately for 5 of 8 participants. The cause of the second elimination phase of total radioactivity was not identified. The sponsor funded both trials.

Trial AIC316-03-I-02: incomplete recovery of the radioactive dose

“The low recovery after the single dose (66%) was most likely related to the formulation used.” (opens the source at this quote in a new tab)
“In Trial 2, the mean overall recovery in excreta samples collected from 0 to 624 hours postdose was incomplete, with only 66.0% of the total dose administered (50.8% in urine and 15.2% in feces).” (opens the source at this quote in a new tab)
“In comparison, in Trial 1 the mean overall recovery was 92% (76.4% in urine and 15.5% in feces).” (opens the source at this quote in a new tab)
“Furthermore, high intersubject variability was observed in fecal excretion of radioactivity for Trial 2 (73%) compared to Trial 1 (24%).” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: causes of incomplete recovery that the authors examined

“The authors postulated a reduced likelihood of complete recovery for compounds with a TRA half-life greater than 50 hours.” (opens the source at this quote in a new tab)
“TRA half-life was 228 and 119 hours in Trial 1 and Trial 2, respectively, but almost complete recovery was reached in Trial 1 (above 90%).” (opens the source at this quote in a new tab)
“Errors in inaccuracy in dose preparation, dose analysis or a combination were investigated as well as noncompliance of sample collection, such as incomplete collection of excreta or missed samples.” (opens the source at this quote in a new tab)
“However, the trial was performed under GCP regulations and no deviations to the protocol procedures were noted.” (opens the source at this quote in a new tab)
“Furthermore, the contribution of the binding to carbonic anhydrase (CA) is small and cannot account for the low recovery of TRA in the current trial.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: slow dissolution of the capsule and incomplete absorption

“Results from dissolution studies (data on file) showed that the HPMC capsule used in Trial 2 had a much lower dissolution rate compared to the clinical tablet formulation used in Trial 1.” (opens the source at this quote in a new tab)
“This likely delayed the time of drug release until the capsule had passed beyond the low pH environment of the stomach required for adequate drug solubility of pritelivir.” (opens the source at this quote in a new tab)
“Furthermore, as the applied homogenization protocol for feces did not accomplish complete dissolution of pritelivir, the non-dissolved pritelivir was not uniformly distributed, as suggested by the high intersubject variability in fecal excretion.” (opens the source at this quote in a new tab)
“Therefore, it was concluded that the HPMC capsule formulation resulted in unexpected slow dissolution, which led to incomplete absorption of pritelivir, resulting in lower systemic exposure.” (opens the source at this quote in a new tab)
“The non-uniform distribution of radioactivity in the feces led to the lower recovery of the administered (radioactive) dose.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-02: lower plasma exposure than in previous trials

“However, the exposure of pritelivir in plasma in Trial 2 was about 2-fold lower compared to previous trials due to incomplete absorption, as discussed below.” (opens the source at this quote in a new tab)
“Despite the incomplete absorption of pritelivir in Trial 2, the percentage pritelivir of TRA remained unchanged (45%-48% for Trial 1 and 41% for Trial 2).” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: metabolites undetectable with one radiolabel position

“Because in the first trial pritelivir was labeled at only 1 position in the molecule, some metabolites remained undetectable.” (opens the source at this quote in a new tab)
“Note that in Trial 1, not all metabolites could be detected because of the position of the radioactive label.” (opens the source at this quote in a new tab)
“ATS was not detected in the HPLC-AMS analysis as it lacked the 14C label at the ATS moiety.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: low extraction efficiency from feces

“Note that due to low extraction efficiency (37.4%) for the feces sample, the reported percentages of pritelivir and metabolites in feces may not fully reflect the absolute proportions of these compounds.” (opens the source at this quote in a new tab)

Trial AIC316-01-I-04: total radioactivity exposure and half-life not accurately determined

“The mean t1/2z for pritelivir was 63 hours and about 228 hours for TRA, although for the latter t1/2z could not be determined accurately (Table 1).” (opens the source at this quote in a new tab)
“Based on the geometric mean ratio AUCτ,ss (pritelivir) to AUC0-inf (TRA) or AUC0-last (since AUC0-inf could not be accurately determined for 5 out of 8 subjects), about 45% or 48% of the radioactivity measured in plasma was attributable to 14C-labeled pritelivir with the remainder being metabolites.” (opens the source at this quote in a new tab)

Second elimination phase of total radioactivity of unidentified cause

“For TRA, a second elimination phase was observed after 336 hours postdose up to 624 hours, which was more obvious in Trial 1.” (opens the source at this quote in a new tab)
“This might suggest an additional, terminal elimination phase of pritelivir or the presence of 1 or more metabolites with long half-lives.” (opens the source at this quote in a new tab)
“However, the cause was not identified as only TRA was measured in samples beyond 324 hours postdose.” (opens the source at this quote in a new tab)
“This second elimination phase could not be observed for pritelivir because the last sample was collected 336 hours postdose on day 8.” (opens the source at this quote in a new tab)

Funding and author affiliations

“These trials were funded by AiCuris Anti-infective Cures AG.” (opens the source at this quote in a new tab)
“Susanne Bonsmann, Dirk Kropeit, Melanie Sumner, Alexander Birkmann, and Holger Zimmermann are current employees of AiCuris Anti-infective Cures AG.” (opens the source at this quote in a new tab)
“David McCormick and Jörg Pausch were employed by AiCuris Anti-infective Cures AG at the time of the trials.” (opens the source at this quote in a new tab)
“Michiel de Vries is an independent clinical pharmacology consultant and owner of Molenpad ClinPharm Support.” (opens the source at this quote in a new tab)