In vitro findings that prompted the clinical interaction trials

“The results of the in vitro studies indicated a potential clinically relevant effect of pritelivir on CYP2C8, CYP2C9, intestinal uptake transporter Organic Anion Transporting Polypeptide 2B1 (OATP2B1) and intestinal efflux transporter Breast Cancer Resistance Protein (BCRP) inhibition, CYP2B6 induction, and CYP3A4/5 suppression.” (opens the source at this quote in a new tab)
“Two clinical trials were performed to further investigate the DDI potential of pritelivir in vivo.” (opens the source at this quote in a new tab)

Perpetrator mechanisms evaluated in both trials

“Two clinical trials were therefore performed to evaluate the in vivo potential of pritelivir as a perpetrator drug, to inhibit CYP2C8 and CYP2C9, induce CYP2C8 and CYP2B6, suppress CYP3A4/5, and inhibit OATP2B1 and BCRP.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: substrates of CYP2C9, CYP2B6, CYP3A4, and OATP2B1

“In the first trial (AIC316-03-I-03; Trial 03) the possible interaction (induction or inhibition) of pritelivir with substrates for CYP2C9, CYP2B6, CYP3A4, and OATP2B1 was investigated.” (opens the source at this quote in a new tab)
“The CYP2C9 substrate flurbiprofen, the CYP2B6 substrate bupropion, and the CYP3A4 substrate midazolam were administered simultaneously as part of the Geneva cocktail.” (opens the source at this quote in a new tab)
“Celiprolol, a substrate for OATP2B1, was administered separately from the cocktail.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: substrates of CYP2C8 and BCRP

“In the second trial (AIC316-03-I-06; Trial 06), the possible interaction of pritelivir with substrates for CYP2C8 and BCRP was investigated.” (opens the source at this quote in a new tab)
“The CYP2C8 substrate repaglinide and the BCRP substrate rosuvastatin were administered separately.” (opens the source at this quote in a new tab)

Expectation for pritelivir as a substrate of CYP enzymes and efflux transporters

“Therefore, pritelivir is not expected to be a sensitive substrate for drug-drug interactions (DDIs) through CYP enzymes.” (opens the source at this quote in a new tab)
“Furthermore, pritelivir was considered to be a substrate for P-glycoprotein (P-gp) and BCRP.” (opens the source at this quote in a new tab)
“interactions of pritelivir as the substrate for P-gp and BCRP are not expected to impact the oral permeability to a clinically relevant extent.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: trial site and ethics committee

“Trial AIC316-03-I-03 (Trial 03) was conducted by PRA Health Sciences Groningen, The Netherlands, and approved by the independent ethics committee Stichting Beoordeling Ethiek Biomedisch Onderzoek (BEBO) Assen, The Netherlands.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: trial site and ethics committee

“Trial AIC316-03-I-06 (Trial 06) was conducted by Nuvisan GmbH, Neu-Ulm, Germany, and approved by the independent ethics committee Ethik-Kommission der Bayrischen Landesärztekammer, München, Germany.” (opens the source at this quote in a new tab)

Conduct standards and consent in both trials

“Both trial protocols and amendments were approved by an ethics committee.” (opens the source at this quote in a new tab)
“An IEC-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, the 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 AIC316-03-I-03: sequential, single-center, open-label phase 1 design

“Trial 03. This was a sequential, single-center, open-label phase 1 trial in 16 healthy male or female subjects.” (opens the source at this quote in a new tab)
“The OATP2B1 substrate celiprolol (200 mg) was administered on days 1 and 8 and a cocktail of substrates, including 10 mg flurbiprofen (CYP2C9 substrate), 20 mg bupropion (CYP2B6 substrate), and 1 mg midazolam (CYP3A4 substrate), was administered on days 3 and 19.” (opens the source at this quote in a new tab)
“A loading dose of 400 mg of pritelivir was administered on day 6, followed by once-daily administrations of 100 mg of pritelivir from day 7 to day 21, inclusive.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: screening, confinement, and end-of-trial visit

“For each subject, the screening examination took place within 4 weeks before trial mediation.” (opens the source at this quote in a new tab)
“Subjects were hospitalized from day −1 until day 25 (at least 96 hours after the last pritelivir administration) and returned to the clinic for an end-of-trial (EOT) visit between days 28 and 35.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: pharmacokinetic sampling schedule

“Serial blood samples (3 mL at each time point) for determination of celiprolol in plasma were taken on days 1 and 8 at predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 36 hours postdose.” (opens the source at this quote in a new tab)
“Serial blood samples (3 mL at each time point) for determination of flurbiprofen, 4-hydroxy-flurbiprofen (OH-flurbiprofen), bupropion, 4-hydroxy-bupropion (OH-bupropion), and midazolam in plasma were taken on days 3 and 19 at predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours postdose.” (opens the source at this quote in a new tab)
“Predose blood samples (3 mL at each time point) for determination of pritelivir in plasma and its metabolites PPA and ATS were taken predose on days 8, 9, 17, 18, 19, and 20.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: sequential, single-center, open-label phase 1 design

“Trial 06. This was a sequential, single-center, open-label phase 1 trial in 16 healthy male or female subjects.” (opens the source at this quote in a new tab)
“The CYP2C8 substrate repaglinide (0.5 mg) was administered on days 1, 7, and 20 and the BCRP substrate rosuvastatin (20 mg) was administered on days 2 and 9.” (opens the source at this quote in a new tab)
“A loading dose of 400 mg of pritelivir was administered on day 7, followed by once-daily administrations of 100 mg of pritelivir from day 8 to day 20, inclusive.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: repaglinide given with the loading dose and again at steady state

“The in vitro studies showed potential for both inhibition and induction of CYP2C8, therefore repaglinide was also administered in combination with the single 400 mg pritelivir loading dose to evaluate its inhibition potential and exclude any bias due to induction.” (opens the source at this quote in a new tab)
“The net effect of inhibition and induction of CYP2C8 was evaluated after 2 weeks under steady-state conditions.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: screening, confinement, and end-of-trial visit

“For each subject, the screening examination took place within 3 weeks before trial mediation.” (opens the source at this quote in a new tab)
“Subjects were hospitalized from day −1 until day 24 (at least 96 hours after the last pritelivir administration) and returned to the clinic for an EOT visit between days 27 and 34.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: pharmacokinetic sampling schedule

“Serial blood samples (3 mL at each time point) for determination of repaglinide in plasma were taken on days 1, 7, and 20 at predose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours postdose.” (opens the source at this quote in a new tab)
“Serial blood samples (3 mL at each time point) for determination of rosuvastatin in plasma were taken on days 2 and 9 at predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours postdose.” (opens the source at this quote in a new tab)
“Predose blood samples (3.4 mL at each time point) for determination of pritelivir in plasma and its metabolites PPA and ATS were taken predose on days 9, 10, 17, 18, 19, and 20.” (opens the source at this quote in a new tab)

Substrates given under steady-state pritelivir at the therapeutic dose

“The substrates were administered alone or in combination with pritelivir under steady-state conditions of the therapeutic dose (100 mg), except for repaglinide.” (opens the source at this quote in a new tab)
“PK parameters (Cmax, AUC0-last, and AUC0-inf) of the substrates and their metabolites (flurbiprofen and bupropion only) were compared after administration in combination with pritelivir (test) versus administration alone (reference).” (opens the source at this quote in a new tab)

Bioanalytical methods and lower limits of quantification for pritelivir and its metabolites

“All analyses were undertaken using fully validated procedures.” (opens the source at this quote in a new tab)
“Plasma concentrations of pritelivir, PPA, and ATS were determined using a validated mass spectrometry high-performance liquid chromatography method (HPLC-MS/MS) by A&M Labor für Analytik und Metabolismusforschung Service GmbH (Germany).” (opens the source at this quote in a new tab)
“The lower limits of quantification (LLOQs) for pritelivir, PPA, and ATS in plasma were 10.0, 2.0, and 2.0 ng/mL, respectively.” (opens the source at this quote in a new tab)

Bioanalytical methods for the probe substrates

“Plasma concentrations of celiprolol, midazolam, flurbiprofen, 4′-hydroxy flurbiprofen (OH-flurbiprofen), bupropion, and hydroxy bupropion (OH-bupropion) were determined using a validated HPLC-MS/MS by A&M Labor für Analytik und Metabolismusforschung Service GmbH (Germany).” (opens the source at this quote in a new tab)
“Plasma concentrations of repaglinide were determined using a validated mass spectrometry ultraperformance liquid chromatography method (UPLC-MS/MS) by Nuvisan GmbH (Germany).” (opens the source at this quote in a new tab)

Inclusion criteria in both trials: healthy adults aged 18 to 55 years

“Healthy male and female subjects of any ethnic origin, aged between 18 and 55 years inclusive with a body mass index between ≥18.0 and ≤30.0 kg/m2 and weighing ≥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 chemical, hematological, or any other laboratory values.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: exclusion of CYP2C9 poor metabolizers

“subjects with poor metabolizer status for CYP2C9, based on genotyping analysis at screening, were excluded in Trial 03 (ie, subjects with any combination of the CYP2C9 *2, *3, *5, and *6 alleles were excluded and subjects genotyped as CYP2C9*1/*5 or CYP2C9*1/*6 were excluded).” (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 before drug administration.” (opens the source at this quote in a new tab)
“Concomitant medications were not allowed throughout the trial except for 500 mg paracetamol (not exceeding 1 g per day) 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 aliments and beverages within 2 weeks before dosing 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 24 hours before dosing until discharge.” (opens the source at this quote in a new tab)
“Subjects were excluded when smoking more than 10 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 AIC316-03-I-03: probe substrate doses and dosing days

Probe substrate	Dose and dosing days
Celiprolol (OATP2B1)	“The OATP2B1 substrate celiprolol (200 mg) was administered on days 1 and 8”
Flurbiprofen (CYP2C9)	“10 mg flurbiprofen (CYP2C9 substrate)”
Bupropion (CYP2B6)	“20 mg bupropion (CYP2B6 substrate)”
Midazolam (CYP3A4)	“1 mg midazolam (CYP3A4 substrate)”
Cocktail dosing days	“was administered on days 3 and 19”

Trial AIC316-03-I-03: pritelivir regimen and administration conditions

“A loading dose of 400 mg of pritelivir was administered on day 6, followed by once-daily administrations of 100 mg of pritelivir from day 7 to day 21, inclusive.” (opens the source at this quote in a new tab)
“Pritelivir was administered orally 1 hour before breakfast or 2 hours after breakfast with 240 mL of water.” (opens the source at this quote in a new tab)
“On PK sampling days (days 8, 17, and 19), subjects received the first meal 4 hours after dosing.” (opens the source at this quote in a new tab)
“Celiprolol and the cocktail of substrates were administered after an overnight fast, with 240 mL of water, and subjects received the first meal 4 hours after dosing.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: probe substrate doses and dosing days

“The CYP2C8 substrate repaglinide (0.5 mg) was administered on days 1, 7, and 20 and the BCRP substrate rosuvastatin (20 mg) was administered on days 2 and 9.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: pritelivir regimen and administration conditions

“A loading dose of 400 mg of pritelivir was administered on day 7, followed by once-daily administrations of 100 mg of pritelivir from day 8 to day 20, inclusive.” (opens the source at this quote in a new tab)
“Pritelivir was administered orally after an overnight fast, 1 hour before breakfast or 2 hours after breakfast, with 240 mL of water.” (opens the source at this quote in a new tab)
“On PK sampling days (days 1, 2, 7, 9, 18, and 20), subjects received the first meal 4 hours after dosing.” (opens the source at this quote in a new tab)
“Repaglinide and rosuvastatin were administered after an overnight fast, with 240 mL of water, and subjects received the first meal 4 hours after dosing.” (opens the source at this quote in a new tab)
“Pritelivir was administered orally 1 hour before breakfast or 2 hours after breakfast, except for day 18 on which subjects were fasted overnight until 4 hours after dosing.” (opens the source at this quote in a new tab)

Pritelivir trough concentrations confirming steady state in both trials

“Mean predose (Ctrough) plasma concentrations of pritelivir, PPA, and ATS were constant over time for both trials, confirming the attainment of steady state.” (opens the source at this quote in a new tab)
“Pritelivir trough concentrations (days 8, 9 and 17, 18, 19 and 20 for Trial 03 and days 9, 10, 17, 18, 19, and 20 for Trial 06) confirmed that the interaction of pritelivir with drug transporters and CYP substrates was evaluated under steady-state conditions within the therapeutic range.” (opens the source at this quote in a new tab)

Exposure comparison with and without pritelivir

“Exposure parameters of the substrates and their metabolites (flurbiprofen and bupropion only) were compared after administration with or without pritelivir under therapeutic concentrations.” (opens the source at this quote in a new tab)

Pharmacokinetic parameters calculated in both trials

“For both trials PK analyses were performed with standard noncompartmental methods using the validated computer program Phoenix® WinNonlin® (version 8.1.1; Certara LP).” (opens the source at this quote in a new tab)
“The following PK parameters were calculated for celiprolol, flurbiprofen, OH-flurbiprofen, bupropion and OH-bupropion, midazolam, repaglinide, and rosuvastatin: Cmax, tmax, AUC0-last, AUC0-inf, t1/2z, and CLss/F (not for OH-flurbiprofen and OH-bupropion).” (opens the source at this quote in a new tab)
“In addition, for OH-flurbirofen and OH-bupropion the m/p ratios of AUC0-last (ratio AUC0-last,m/p) and AUC0-inf (ratio AUC0-inf,m/p) were calculated.” (opens the source at this quote in a new tab)
“For pritelivir, PPA and ATS in plasma, Ctrough was calculated.” (opens the source at this quote in a new tab)

No-effect boundary of 80% to 125% for the 90% confidence interval

“For the interpretation of the results, a no-effect boundary of 80%-125% was used for the 90% CIs of the LSmeans ratios of the exposure parameters (Cmax, AUC0-last, and AUC0-inf).” (opens the source at this quote in a new tab)
“Although it was not powered to show the absence of an effect, the generally accepted no-effect boundaries of 80%-125% for the 90% CIs for systemic exposure ratios were used for the interpretation of the results.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: selection of the Geneva cocktail substrates

“To assess the effects on CYP2C9, CYP2B6, and CYP3A4 in Trial 03, the substrates flurbiprofen, bupropion, and midazolam were administered simultaneously as part of the validated Geneva cocktail” (opens the source at this quote in a new tab)
“The components of this validated cocktail have been shown not to interfere with their respective metabolisms” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: selection of celiprolol as the OATP2B1 substrate

“There is no specific substrate for OATP2B1.” (opens the source at this quote in a new tab)
“Celiprolol, aliskiren, atenolol, nizatidine, fexofenadine, and ciprofloxacin are substrates of the OATP2B1.” (opens the source at this quote in a new tab)
“Common juices are potent inhibitors of intestinal OATP2B1.” (opens the source at this quote in a new tab)
“Celiprolol was selected as the OATP2B1 substrate in Trial 03 because it is most sensitive for inhibition of intestinal OATP2B1 by common juices, resulting in an approximately 90% decrease in AUC and Cmax” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: selection of repaglinide and rosuvastatin

“The prototypic substrates repaglinide for CYP2C8 and rosuvastatin for BCRP were used as substrates in Trial 06.” (opens the source at this quote in a new tab)

Hydroxy metabolites measured as markers of CYP2C9 and CYP2B6 activity

“Next to bupropion and flurbiprofen as substrates for CYP2C9 and CYP2B6, their hydroxy metabolites (OH-bupropion and OH-flurbiprofen) were measured as well because their formation is mediated by the respective CYP enzymes.” (opens the source at this quote in a new tab)

Safety and tolerability assessments in both trials

“Safety assessments in both trials consisted of AE 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 24.1 for Trial 03 and version 25.0 for Trial 06).” (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 subject level (occurrence of at least 1 TEAE), primary system organ class level, and preferred term level.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: planned sample size

“Based on the expected intrasubject coefficient of variation for AUC and Cmax of all substrates, a total of 14 subjects would suffice to characterize with at least 80% power, an interaction of 20% of pritelivir on the substrates.” (opens the source at this quote in a new tab)
“Two additional subjects were added to allow for possible drop-outs.” (opens the source at this quote in a new tab)

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

“In total 16 healthy subjects (9 male, 7 female) were enrolled in the trial.” (opens the source at this quote in a new tab)
“All enrolled subjects received all planned treatments, completed the trial, and were included in the safety and PK population.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: planned sample size

“Based on the expected intrasubject coefficient of variation for AUC and Cmax of all substrates, a total of 14 subjects would suffice to characterize with at least 80% power, an interaction of 25% of pritelivir on the substrates.” (opens the source at this quote in a new tab)
“Two additional subjects were added to allow for possible drop-outs.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: participants enrolled and analyzed

“In total 16 healthy subjects (7 male, 9 female) were enrolled in the trial.” (opens the source at this quote in a new tab)
“All enrolled subjects received all planned treatments, completed the trial, and were included in the safety and PK population.” (opens the source at this quote in a new tab)

Powering of the trials for an interaction of 20% to 25%

“As the results of the in vitro studies suggested potential interactions with all substrates, the trial was powered to characterize an interaction of 20%-25% of pritelivir on the substrates.” (opens the source at this quote in a new tab)

Participants contributing to each descriptive pharmacokinetic parameter

Substrate and treatment	Participants contributing to the parameter
Celiprolol alone (day 1)	“n = 15 for AUC0-inf, t1/2z, and CL/F.”
Midazolam alone (day 3), midazolam with pritelivir (day 19), and rosuvastatin with pritelivir (day 9)	“n = 14 for AUC0-inf, t1/2z, and CL/F.”
OH-flurbiprofen alone (day 3)	“n = 13 for AUC0-inf, t1/2z, and ratioAUC0-inf,m/p.”
OH-flurbiprofen with pritelivir (day 19)	“n = 11 for t1/2z and n = 8 for AUC0-inf and ratio AUC0-inf,m/p.”
Bupropion with pritelivir (day 19)	“n = 13 for AUC0-inf, t1/2z, and CL/F.”
OH-bupropion alone (day 3)	“n = 15 AUC0-last, t1/2z, and ratio AUC0-last,m/p; n = 13 for AUC0-inf and ratio AUC0-inf,m/p.”
OH-bupropion with pritelivir (day 19)	“n = 14 for t1/2z; n = 13 for AUC0-inf; n = 10 for ratio AUC0-inf,m/p.”
Repaglinide alone (day 1)	“n = 4 for AUC0-inf, t1/2z, and CL/F.”
Repaglinide with pritelivir (day 7)	“n = 7 for AUC0-inf, t1/2z, and CL/F.”
Repaglinide with pritelivir (day 20)	“n = 8 for AUC0-inf, t1/2z, and CL/F.”
Rosuvastatin alone (day 2)	“n = 9 for AUC0-inf, t1/2z, and CL/F.”

Safety and pharmacokinetic population in both trials

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

Trial AIC316-03-I-03: linear mixed-effects model

“To evaluate the effect of pritelivir on the PK of the substrates, a linear mixed-effects model was applied on the log-transformed parameters AUC0-inf, AUC0-last, and Cmax of celiprolol, flurbiprofen, bupropion, and midazolam, and ratio AUC0-last,m/p and ratio AUC0-inf,m/p of OH-flurbiprofen and OH-bupropion (a separate model per substrate) with treatment (day) as a fixed effect and subject as a random effect.” (opens the source at this quote in a new tab)
“Both the difference between the LSmeans and the 90% CIs were retransformed to the original scale.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: linear mixed-effects model

“To evaluate the effect of pritelivir on the PK of the substrates, a linear mixed-effects model was applied on the log-transformed parameters AUC0-inf, AUC0-last, and Cmax of repaglinide and rosuvastatin (a separate model per substrate) with treatment (day) as a fixed effect and subject as a random effect.” (opens the source at this quote in a new tab)

Test and reference treatments for the least square means ratios

Role in the ratio	Treatment as named by the authors
Test	“substrate with pritelivir”
Reference	“substrate without pritelivir”

Trial AIC316-03-I-03: sensitivity analysis of celiprolol excluding one participant

“For celiprolol, the analysis was performed with and without subject 107, who suffered from adverse events (AEs) potentially impacting exposure parameters.” (opens the source at this quote in a new tab)
“As subject 107 suffered from AEs between day −1 and day 3, a sensitivity analysis on celiprolol PK parameters was performed excluding subject 107.” (opens the source at this quote in a new tab)

Descriptive statistics and handling of concentrations below the limit of quantification

“Descriptive statistics were calculated for the PK parameters 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)
“All samples below the LLOQ were entered as 0 and included as such in the calculation of means.” (opens the source at this quote in a new tab)

Rules for excluding a parameter from descriptive statistics

“PK parameters AUC0-inf, t1/2z, and CL/F were excluded from descriptive statistics if less than 3 data points were used in the calculation (not including Cmax), coefficient of determination (r2adj) was <0.850, the span of time points (λz upper − λz lower) was less than twice the calculated t1/2z.” (opens the source at this quote in a new tab)
“AUC0-last was excluded if actual time of the last sample was missing.” (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)

Trial AIC316-03-I-03: all 16 participants completed

“In total 16 healthy subjects (9 male, 7 female) were enrolled in the trial.” (opens the source at this quote in a new tab)
“All enrolled subjects received all planned treatments, completed the trial, and were included in the safety and PK population.” (opens the source at this quote in a new tab)
“All the TEAEs were of mild intensity, none were serious, and no subjects discontinued trial medication or withdrew from the trial due to TEAEs.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: all 16 participants completed

“In total 16 healthy subjects (7 male, 9 female) were enrolled in the trial.” (opens the source at this quote in a new tab)
“All enrolled subjects received all planned treatments, completed the trial, and were included in the safety and PK population.” (opens the source at this quote in a new tab)
“The majority of the TEAEs were of mild intensity, none were serious, and no subjects discontinued trial medication or withdrew from the trial due to TEAEs.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: sex, age, body weight, and body mass index

“In total 16 healthy subjects (9 male, 7 female) were enrolled in the trial.” (opens the source at this quote in a new tab)
“The mean age was 35.4 years (range 22-55), mean body weight was 75.1 kg (range 54.7-99.8), and mean body mass index (BMI) was 23.9 kg/m2 (range 19.1-28.8 kg/m2).” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: CYP2C9 genotype

“Based on the results of genotyping, none of the subjects participating in the trial was predicted to be a poor metabolizer for CYP2C9.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: sex, age, body weight, and body mass index

“In total 16 healthy subjects (7 male, 9 female) were enrolled in the trial.” (opens the source at this quote in a new tab)
“Mean age was 43.6 years (range 25-55), mean body weight was 70.2 kg (range 52.7-88.0), and mean BMI was 24.1 kg/m2 (range 19.0-29.7 kg/m2).” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: least square means ratios for OATP2B1, CYP3A4, CYP2C9, and CYP2B6 substrates

Substrate and parameter	n	Without pritelivir (reference)	With pritelivir (test)	LSmeans ratio (%)	90% CI (%)
Celiprolol (OATP2B1), Cmax (ng/mL)	“16”	“540”	“743”	“137.6”	“89.1-212.3”
Celiprolol (OATP2B1), AUC0-last (ng•h/mL)	“16”	“2827”	“3708”	“131.1”	“97.3-176.8”
Celiprolol (OATP2B1), AUC0-inf (ng•h/mL)	“15”	“3320”	“3756”	“113.1”	“96.3-132.9”
Celiprolol excluding subject 107, Cmax (ng/mL)	“15”	“655”	“733”	“111.9”	“86.5-144.9”
Celiprolol excluding subject 107, AUC0-last (ng•h/mL)	“15”	“3248”	“3678”	“113.3”	“96.1-133.5”
Celiprolol excluding subject 107, AUC0-inf (ng•h/mL)	“15”	“3320”	“3756”	“113.1”	“96.3-132.9”
Midazolam (CYP3A4), Cmax (ng/mL)	“16”	“7.0”	“6.1”	“87.4”	“76.7-99.7”
Midazolam (CYP3A4), AUC0-last (ng•h/mL)	“16”	“16.1”	“14.8”	“91.8”	“82.3-102.3”
Midazolam (CYP3A4), AUC0-inf (ng•h/mL)	“12”	“17.8”	“17.3”	“97.2”	“86.0-109.7”
Flurbiprofen (CYP2C9), Cmax (ng/mL)	“16”	“1873”	“1833”	“97.9”	“93.2-102.7”
Flurbiprofen (CYP2C9), AUC0-last (ng•h/mL)	“16”	“7066”	“8219”	“116.3”	“111.5-121.3”
Flurbiprofen (CYP2C9), AUC0-inf (ng•h/mL)	“16”	“7291”	“8546”	“117.2”	“112.3-122.3”
OH-flurbiprofen, metabolite-to-parent ratio of AUC0-last	“16”	“0.04”	“0.04”	“113.3”	“104.6-122.6”
OH-flurbiprofen, metabolite-to-parent ratio of AUC0-inf	“8”	“0.05”	“0.06”	“113.2”	“98.7-129.9”
Bupropion (CYP2B6), Cmax (ng/mL)	“16”	“39.0”	“37.6”	“96.3”	“77.3-119.9”
Bupropion (CYP2B6), AUC0-last (ng•h/mL)	“16”	“163”	“148”	“90.8”	“81.4-101.3”
Bupropion (CYP2B6), AUC0-inf (ng•h/mL)	“13”	“184”	“178”	“96.9”	“90.2-104.1”
OH-bupropion (CYP2B6), metabolite-to-parent ratio of AUC0-last	“15”	“9.4”	“11.2”	“118.7”	“106.4-132.4”
OH-bupropion (CYP2B6), metabolite-to-parent ratio of AUC0-inf	“9”	“9.5”	“10.5”	“110.9”	“96.2-127.7”

Trial AIC316-03-I-06: least square means ratios for CYP2C8 and BCRP substrates

Substrate and parameter	n	Without pritelivir (reference)	With pritelivir (test)	LSmeans ratio (%)	90% CI (%)
Repaglinide (CYP2C8), day 7, Cmax (ng/mL)	“16”	“7.7”	“7.6”	“97.9”	“80.3-119.2”
Repaglinide (CYP2C8), day 7, AUC0-last (ng•h/mL)	“16”	“9.9”	“11.4”	“115.5”	“102.9-129.6”
Repaglinide (CYP2C8), day 7, AUC0-inf (ng•h/mL)	“3”	“13.8”	“13.7”	“99.4”	“75.9-130.1”
Repaglinide (CYP2C8), day 20, Cmax (ng/mL)	“16”	“7.7”	“8.7”	“113.2”	“92.9-137.9”
Repaglinide (CYP2C8), day 20, AUC0-last (ng•h/mL)	“16”	“9.9”	“12.6”	“127.5”	“113.6-143.1”
Repaglinide (CYP2C8), day 20, AUC0-inf (ng•h/mL)	“3”	“13.8”	“15.6”	“113.5”	“86.6-148.5”
Rosuvastatin (BCRP), Cmax (ng/mL)	“16”	“7.1”	“11.9”	“167.0”	“145.2-192.0”
Rosuvastatin (BCRP), AUC0-last (ng•h/mL)	“16”	“81.1”	“115”	“141.3”	“128.0-155.9”
Rosuvastatin (BCRP), AUC0-inf (ng•h/mL)	“8”	“84.4”	“116”	“136.9”	“126.6-147.9”

Trial AIC316-03-I-03: celiprolol and the OATP2B1 interaction

“The LSmeans ratios of Cmax, AUC0-last, and AUC0-inf after administration of celiprolol with pritelivir (day 8, test) compared with celiprolol alone (day 1, reference), exceeded 100% (range 111.9%-113.3%, excluding subject 107) and the upper bound of the 90% CIs exceeding the 125% no-effect boundary.” (opens the source at this quote in a new tab)
“Furthermore, no inhibition of the intestinal uptake transporter OATP2B1 was observed.” (opens the source at this quote in a new tab)
“In the case of inhibition of OATP2B1 by pritelivir, a LSmeans ratio below 100% was expected.” (opens the source at this quote in a new tab)
“However, celiprolol LSmeans ratios for Cmax, AUC0-last, and AUC0-inf were slightly increased after administration with pritelivir under steady-state conditions, with the upper bounds of the ratios exceeding the 125% no-effect boundary.” (opens the source at this quote in a new tab)
“As the results of the in vitro studies did not predict a potentially clinically relevant effect on the OATP2B1 hepatic uptake transporter, it is not likely that this caused the slight increase.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: celiprolol exposure in the excluded participant

“For the interpretation of the results, subject 107 was excluded.” (opens the source at this quote in a new tab)
“Subject 107 had a much lower celiprolol exposure (Cmax and AUC) on day 1 compared to the other subjects.” (opens the source at this quote in a new tab)
“In addition, the exposure of subject 107 on day 1 was much lower than on day 8, which was not observed for the other subjects.” (opens the source at this quote in a new tab)
“Subject 107 suffered from diarrhea on days 2 and 3, and other AEs including abdominal discomfort, dizziness, fatigue, and rhinorrhea between days −1 and 2.” (opens the source at this quote in a new tab)
“The gastrointestinal-related AEs might be the origin of the low celiprolol exposure on day 1.” (opens the source at this quote in a new tab)
“The results of the analysis including subject 107 did not change the conclusions.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: midazolam and the CYP3A4 interaction

“The LSmeans ratios of Cmax, AUC0-last, and AUC0-inf after administration of midazolam with pritelivir (day 19, test) compared with midazolam alone (day 3, reference) were similar and the 90% CIs for AUC0-last and AUC0-inf were within the 80%-125% no-effect boundaries.” (opens the source at this quote in a new tab)
“The lower bound of the 90% CI of the Cmax ratio was just below the 80% no-effect boundary.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: flurbiprofen, OH-flurbiprofen, and the CYP2C9 interaction

“The LSmeans ratios of Cmax, AUC0-last, and AUC0-inf after administration of flurbiprofen with pritelivir (day 19, test) compared with flurbiprofen alone (day 3, reference) were similar and their 90% CIs were all included within the 80%-125% no-effect boundaries.” (opens the source at this quote in a new tab)
“The OH-flurbiprofen to flurbiprofen AUC0-last and AUC0-inf LSmeans ratios showed consistent results; the 90% CI of the OH-flurbiprofen to flurbiprofen AUC0-last ratio was within the no-effect boundaries of 80%-125%, but the upper bound of the 90% CI of the OH-flurbiprofen to flurbiprofen AUC0-inf ratio slightly exceeded the 125% no-effect boundary.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: bupropion, OH-bupropion, and the CYP2B6 interaction

“The LSmeans ratios of Cmax, AUC0-last, and AUC0-inf after administration of bupropion with pritelivir (day 19, test) compared with bupropion alone (day 3, reference) were similar and the 90% CIs for AUC0-last and AUC0-inf were within the 80%-125% no-effect boundaries.” (opens the source at this quote in a new tab)
“The OH-bupropion to bupropion AUC0-last and AUC0-inf LSmeans ratios showed consistent results, but the upper bounds of the 90% CIs slightly exceeded the 125% no-effect boundary.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: repaglinide with the 400 mg loading dose (CYP2C8 inhibition)

“The LSmeans ratios of Cmax, AUC0-last, and AUC0-inf after administration of repaglinide with pritelivir (day 7, test) compared with repaglinide alone (day 1, reference) were around 100%.” (opens the source at this quote in a new tab)
“The upper bounds of the 90% CIs slightly exceeded the 125% no-effect boundary for AUC0-last and slightly exceeded both the upper and lower bounds of the no-effect boundaries for AUC0-inf (n = 3).” (opens the source at this quote in a new tab)
“For Cmax, the 90% CIs were within the 80%-125% no-effect boundaries.” (opens the source at this quote in a new tab)
“For CYP2C8 (repaglinide), there was no clinically relevant inhibition observed when combined with the 400 mg loading dose of pritelivir.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: repaglinide at pritelivir steady state (net CYP2C8 inhibition and induction)

“The LSmeans ratios of Cmax, AUC0-last, and AUC0-inf (n = 3) of repaglinide were slightly increased (range 113.2-127.5) after administration of multiple doses of pritelivir (400 mg on day 7 followed by 100 mg once daily (qd) from days 8 to 20; day 20, test) compared with repaglinide alone (day 1, reference).” (opens the source at this quote in a new tab)
“The upper bounds of the 90% CIs all exceeded the 125% no-effect boundary.” (opens the source at this quote in a new tab)
“When combined with 100 mg pritelivir at steady state, there was no net induction of CYP2C8 activity, but as the upper bound of the 90% CIs exceeded the 125% no-effect boundary, a weak net inhibition of CYP2C8 cannot be excluded.” (opens the source at this quote in a new tab)
“However, as the LSmeans ratio for Cmax was far below 125% (113.2%) and the LSmeans ratio for AUC0-last was just above 125% (127.5%), this is likely not of clinical relevance.” (opens the source at this quote in a new tab)
“Thus, the combined results of the effects of single and multiple doses of pritelivir on the pharmacokinetics of the CYP2C8 substrate repaglinide indicate that pritelivir does not have a clinically relevant effect on CYP2C8.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: rosuvastatin and the BCRP interaction

“The LSmeans ratios of Cmax, AUC0-last, and AUC0-inf (n = 8) after administration of rosuvastatin with pritelivir (day 9, test) compared with rosuvastatin alone (day 2, reference) exceeded 100% (136.9% and 167.0% for AUC0-last and Cmax, respectively) and the lower and upper bounds of the 90% CIs both exceeded the 125% no-effect boundary.” (opens the source at this quote in a new tab)
“Consistent with the in vitro results, a therapeutic 100-mg multiple once-daily regimen of pritelivir showed a weak inhibitory potential on the intestinal efflux transporter BCRP (<2-fold).” (opens the source at this quote in a new tab)
“When combined with 400 mg of pritelivir on day 7 followed by 100 mg once daily on day 9, the LSmeans ratios for Cmax, AUC0-last, and AUC0-inf of rosuvastatin were increased (167.0, 141.3, and 136.9, respectively) and the lower bound of the CI exceeded the 125% no-effect boundary.” (opens the source at this quote in a new tab)
“Although there is no standard classification for the effects of transporter inhibitors, the increase in rosuvastatin is analogous to weak inhibition in the scenario of CYP inhibition with a sensitive substrate” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: descriptive pharmacokinetic parameters of the parent substrates

Substrate and treatment	n	Cmax (ng/mL)	tmax (hour)	AUC0-last (ng•h/mL)	AUC0-inf (ng•h/mL)	t1/2z (hour)	CL/F (L/h)
Celiprolol alone (day 1)	“16”	“707 (430)”	“5.0 (3.0-6.0)”	“3312 (1524)”	“3579 (1355)”	“5.3 (1.1)”	“65.4 (28.2)”
Celiprolol + pritelivir (day 8)	“16”	“807 (318)”	“5.0 (2.0-6.0)”	“3881 (1082)”	“3952 (1078)”	“5.8 (0.8)”	“56.2 (24.5)”
Midazolam alone (day 3)	“16”	“7.3 (2.1)”	“0.5 (0.3-0.8)”	“16.7 (4.7)”	“17.6 (5.1)”	“4.1 (1.4)”	“61.6 (18.4)”
Midazolam + pritelivir (day 19)	“16”	“6.5 (2.1)”	“0.5 (0.5-1.1)”	“15.7 (5.3)”	“17.4 (5.1)”	“3.7 (1.3)”	“64.2 (25.7)”
Flurbiprofen alone (day 3)	“16”	“1892 (260)”	“0.5 (0.3-0.5)”	“7356 (2158)”	“7588 (2226)”	“5.5 (1.5)”	“1.4 (0.4)”
Flurbiprofen + pritelivir (day 19)	“16”	“1861 (323)”	“0.5 (0.3-0.8)”	“8577 (2542)”	“8901 (2579)”	“6.3 (1.8)”	“1.2 (0.4)”
Bupropion alone (day 3)	“16”	“43.1 (19.6)”	“1.0 (0.5-2.0)”	“173 (58.6)”	“193 (66.0)”	“11.9 (4.9)”	“116 (42.1)”
Bupropion + pritelivir (day 19)	“16”	“41.1 (16.2)”	“1.0 (0.8-2.0)”	“157 (54.4)”	“188 (64.7)”	“12.5 (5.0)”	“119 (42.5)”

Trial AIC316-03-I-03: descriptive pharmacokinetic parameters of the hydroxy metabolites

Metabolite and treatment	n	Cmax (ng/mL)	tmax (hour)	AUC0-last (ng•h/mL)	AUC0-inf (ng•h/mL)	t1/2z (hour)	Ratio AUC0-last,m/p	Ratio AUC0-inf,m/p
OH-flurbiprofen alone (day 3)	“16”	“79.2 (24.0)”	“0.8 (0.5-0.8)”	“305 (92.2)”	“380 (90.7)”	“3.4 (0.8)”	“0.04 (0.02)”	“0.05 (0.01)”
OH-flurbiprofen + pritelivir (day 19)	“16”	“77.4 (24.6)”	“0.8 (0.5-1.5)”	“400 (126)”	“513 (109)”	“4.4 (1.0)”	“0.05 (0.02)”	“0.06 (0.01)”
OH-bupropion alone (day 3)	“16”	“56.9 (22.3)”	“4.5 (2.0-5.0)”	“1806 (851)”	“1787 (691)”	“24.6 (5.2)”	“9.9 (3.1)”	“9.7 (3.3)”
OH-bupropion + pritelivir (day 19)	“16”	“61.5 (24.8)”	“4.0 (2.0-5.0)”	“1911 (917)”	“1918 (729)”	“23.1 (4.9)”	“12.1 (4.9)”	“11.3 (5.0)”

Trial AIC316-03-I-06: descriptive pharmacokinetic parameters of repaglinide and rosuvastatin

Substrate and treatment	n	Cmax (ng/mL)	tmax (hour)	AUC0-last (ng•h/mL)	AUC0-inf (ng•h/mL)	t1/2z (hour)	CL/F (L/h)
Repaglinide alone (day 1)	“16”	“8.4 (3.6)”	“0.6 (0.5-1.3)”	“10.7 (4.2)”	“11.9 (4.0)”	“2.0 (0.1)”	“47.4 (22.2)”
Repaglinide + pritelivir (day 7)	“16”	“8.2 (3.2)”	“0.8 (0.5-2.0)”	“11.9 (3.4)”	“12.6 (3.1)”	“1.6 (0.2)”	“42.3 (12.6)”
Repaglinide + pritelivir (day 20)	“16”	“9.7 (4.4)”	“0.5 (0.3-3.0)”	“13.3 (4.2)”	“12.9 (4.4)”	“1.7 (0.3)”	“43.2 (15.6)”
Rosuvastatin alone (day 2)	“16”	“9.1 (7.6)”	“4.0 (0.5-6.0)”	“91.4 (46.5)”	“101 (49.0)”	“13.2 (1.8)”	“246 (119)”
Rosuvastatin + pritelivir (day 9)	“16”	“14.6 (10.3)”	“4.0 (0.5-6.1)”	“127 (58.3)”	“124 (58.1)”	“12.8 (2.4)”	“195 (86.9)”

Statistics shown in the descriptive parameter tables

“Data are mean (±SD) except for tmax and tlag median (min-max).” (opens the source at this quote in a new tab)

Pritelivir exposure by sex at steady state in both trials

Group	n	AUC0-24h (ng•h/mL)	AUC0-24h adjusted for body weight (ng•h/mL*kg)
All	“32”	“111,937”	“7,984,428”
Male	“16”	“100,331”	“8,045,144”
Female	“16”	“123,542”	“7,912,122”
Ratio F/M	“16”	“1.23”	“0.98”

“A 23% higher AUC0-24 h was observed in females compared to males.” (opens the source at this quote in a new tab)
“This difference was reduced to 2% when adjusting for body weight (Table 3).” (opens the source at this quote in a new tab)
“Furthermore, there was no difference between males and females after adjusting for body weight.” (opens the source at this quote in a new tab)

Authors' conclusions for CYP3A4, CYP2C9, and CYP2B6

“The results from the 2 trials indicate no clinical interaction potential of pritelivir for CYP3A4 (suppression), CYP2C9 (inhibition), and CYP2B6 (induction) as AUC0-last and AUC0-inf of the respective substrates midazolam, flurbiprofen, and bupropion were within the 80%-125% no-effect boundaries.” (opens the source at this quote in a new tab)
“For midazolam and bupropion Cmax, the lower bound of the 90% CI was slightly below the 80% no-effect boundary.” (opens the source at this quote in a new tab)
“The m/p ratios of OH-flurbiprofen and OH-bupropion confirmed these results, but the upper bound of the 90% CI of the m/p ratios for both substrates slightly exceeded the 125% no-effect boundary, except for the AUC0-last ratio of OH-flurbiprofen/flurbiprofen.” (opens the source at this quote in a new tab)

Authors' overall conclusion on the interaction potential of pritelivir

“In conclusion, a therapeutic 100-mg multiple once-daily regimen of pritelivir had no clinically relevant effect on the exposure of substrates for the intestinal uptake transporter OATP2B1 (celiprolol) and the cytochrome P450 enzymes 3A4 (midazolam), 2B6 (bupropion), 2C9 (flurbiprofen), and 2C8 (repaglinide).” (opens the source at this quote in a new tab)
“However, it showed a weak inhibitory potential on the intestinal efflux transporter BCRP.” (opens the source at this quote in a new tab)
“Overall, the results indicate that pritelivir has a low DDI potential.” (opens the source at this quote in a new tab)

Prescribing information: rosuvastatin exposure with pritelivir

“BCRP substrates: Co-administration of multiple pritelivir doses (400 mg on Day 1 followed by 100 mg once daily on Day 2 and Day 3) with a single 20 mg oral dose of rosuvastatin (on Day 3) resulted in a 1.7-fold increase in Cmax and a 1.4-fold increase in AUC of rosuvastatin compared to rosuvastatin administered alone” (opens the prescribing information at this quote)

Co-administered drug and regimen	Pritelivir regimen	N	AUC0-inf geometric mean ratio (90% CI)	AUC0-last geometric mean ratio (90% CI)	Cmax geometric mean ratio (90% CI)
“Rosuvastatin 20 mg single dose”	“100 mg once daily”	“16”	“1.37 (1.27, 1.48)”	“1.41 (1.28, 1.56)”	“1.67 (1.45, 1.92)”

Prescribing information: BCRP substrate interaction statement

“Pritelivir is a breast cancer resistance protein (BCRP) inhibitor.” (opens the prescribing information at this quote)
“Co-administration of HOVILPRI with a BCRP substrate may increase the plasma concentrations of the BCRP substrate” (opens the prescribing information at this quote)
“which may increase the risk of adverse reactions.” (opens the prescribing information at this quote)
“Refer to the prescribing information for co-administered drugs for additional information.” (opens the prescribing information at this quote)

Prescribing information: CYP2B6, CYP2C8, CYP2C9, CYP3A4, and OATP2B1 substrates

“CYP2B6, CYP2C8, CYP2C9, CYP3A4, and OATP2B1 substrates: No clinically significant changes in substrate exposures were observed in clinical drug-drug interaction trials when pritelivir was co-administered with the cytochrome P450 (CYP)2B6 substrate bupropion, the CYP2C8 substrate repaglinide, the CYP2C9” (opens the prescribing information at this quote)
“substrate flurbiprofen, the CYP3A4 substrate midazolam, and the organic anion transporting polypeptide (OATP)2B1 substrate celiprolol.” (opens the prescribing information at this quote)

Comparability of adverse event counts between treatments

“When comparing the number of subjects with TEAEs between different treatments or combinations, it must be considered that the number of treatment days included in the analysis differed between treatments or combinations, preventing a truly like-for-like comparison.” (opens the source at this quote in a new tab)

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

“Overall, 13 out of 16 subjects (81.3%) had at least 1 TEAE during at least 1 treatment period.” (opens the source at this quote in a new tab)
“All the TEAEs were of mild intensity, none were serious, and no subjects discontinued trial medication or withdrew from the trial due to TEAEs.” (opens the source at this quote in a new tab)
“Overall, 3 TEAEs in 3 subjects were not considered to be recovered at the end of the trial, none of these were considered to be related to any trial medication.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: adverse events considered related to trial medication

“The TEAEs reported as related to multiple-dose 100 mg pritelivir were all gastrointestinal disorders, including abdominal discomfort, abdominal distention, and diarrhea.” (opens the source at this quote in a new tab)
“The TEAEs related to the combination of a single dose of cocktail and pritelivir 100 mg qd were also gastrointestinal disorders, including abdominal discomfort and nausea.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: vital signs, electrocardiograms, and laboratory parameters

“No effects were apparent in vital signs, ECGs, or physical examination findings.” (opens the source at this quote in a new tab)
“Clinical laboratory parameters showed no clinically relevant findings.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: treatment-emergent adverse events

“Overall, 9 out of 16 subjects (56.3%) had at least 1 TEAE during at least 1 treatment period.” (opens the source at this quote in a new tab)
“The majority of the TEAEs were of mild intensity, none were serious, and no subjects discontinued trial medication or withdrew from the trial due to TEAEs.” (opens the source at this quote in a new tab)
“All events were reported recovered/resolved by the end of the trial.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: moderate-intensity events and events considered related

“Three subjects experienced a total of 4 moderate-intensity TEAEs.” (opens the source at this quote in a new tab)
“These events occurred during treatment with rosuvastatin 20 mg (back pain), pritelivir 100 mg qd (abdominal pain lower and nasopharyngitis), and rosuvastatin 20 mg + pritelivir 100 mg qd (headache).” (opens the source at this quote in a new tab)
“The moderate event of headache was considered by the investigator to be related to rosuvastatin; the other moderate intensity events were not considered to be related to trial medication.” (opens the source at this quote in a new tab)
“One TEAE (rash of mild intensity) was reported as related to pritelivir alone 100 mg qd.” (opens the source at this quote in a new tab)

Authors' conclusion on safety and tolerability in both trials

“Pritelivir was safe and well tolerated in healthy volunteers when administered as a single oral 400 mg loading dose, followed by doses of 100 mg alone or in combination with single doses of celiprolol 200 mg, midazolam 1 mg, flurbiprofen 10 mg, or bupropion 20 mg or in combination with single doses of repaglinide 0.5 mg or rosuvastatin 20 mg.” (opens the source at this quote in a new tab)

Summary

Both trials were single-center, open-label, sequential phase 1 trials, each enrolling 16 healthy participants (age range 22 to 55 years in Trial 03 and 25 to 55 years in Trial 06). Each was sized to characterize an interaction of 20% or 25%, and the authors state the trials were not powered to show the absence of an effect. AUC0-inf ratios were based on 3 of 16 participants for repaglinide and 8 of 16 for rosuvastatin. Celiprolol is also a P-glycoprotein substrate and rosuvastatin is also an OATP2B1 substrate. Treatment days differed between treatments, which limits comparison of adverse event counts. The sponsor funded both trials, and 5 authors are its employees.

Trials powered to characterize an interaction and to interpret it against no-effect boundaries

“Although it was not powered to show the absence of an effect, the generally accepted no-effect boundaries of 80%-125% for the 90% CIs for systemic exposure ratios were used for the interpretation of the results.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-03: celiprolol as a non-specific OATP2B1 substrate

“Celiprolol is not a specific substrate for OATP2B1: in vitro and pharmacogenomic studies suggest that celiprolol is also a substrate of the efflux transporter P-gp” (opens the source at this quote in a new tab)
“This did not affect the interpretation of the results, since pritelivir is not an inhibitor or inducer of P-gp.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: rosuvastatin as a substrate of both BCRP and OATP2B1

“Rosuvastatin is also a known substrate for OATP2B1.” (opens the source at this quote in a new tab)
“This does not affect the interpretation of results since in Trial 03 it was shown that pritelivir is not an OATP2B1 inhibitor in vivo.” (opens the source at this quote in a new tab)

Trial AIC316-03-I-06: weak net inhibition of CYP2C8 at steady state

“When combined with 100 mg pritelivir at steady state, there was no net induction of CYP2C8 activity, but as the upper bound of the 90% CIs exceeded the 125% no-effect boundary, a weak net inhibition of CYP2C8 cannot be excluded.” (opens the source at this quote in a new tab)

Absence of a standard classification for transporter inhibition

“Although there is no standard classification for the effects of transporter inhibitors, the increase in rosuvastatin is analogous to weak inhibition in the scenario of CYP inhibition with a sensitive substrate” (opens the source at this quote in a new tab)

Unequal treatment days in the adverse event comparison

“When comparing the number of subjects with TEAEs between different treatments or combinations, it must be considered that the number of treatment days included in the analysis differed between treatments or combinations, preventing a truly like-for-like comparison.” (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)
“Dirk Kropeit, Susanne Bonsmann, Melanie Sumner, Alexander Birkmann, and Holger Zimmermann are employees of AiCuris Anti-infective Cures AG.” (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)