Product information and disease description Product description Product information Pharmacology

Pharmacokinetics

19 evidence topics · 7 sources

Pharmacokinetic properties of pritelivir: prescribing information

Parameter	Prescribing information
Absolute bioavailability	“72%”
Time to maximum concentration, mean (range), at 100 mg once daily	“3 h (2.0–4.5 h)”
Food effect on exposure	“AUC ratio fed/fasted: 1.16”
Food effect on maximum concentration	“Cmax ratio fed/fasted: 1.33”
Apparent volume of distribution (Vd/F), geometric mean (%CV)	“64.1 L (37.3%)”
Plasma protein binding	“97.3%”
Blood-to-plasma ratio, mean, at 100 mg once daily	“AUC: 1.86”
Metabolism	“Pritelivir is primarily metabolized by non-enzymatic hydrolysis to its major inactive metabolites, AIC090015 (26.3%)”
Second major inactive metabolite	“AIC090105 (14.4%)”
Percentage of dose excreted in urine	“76.4% (0.6% unchanged)”
Percentage of dose excreted in feces	“15.5% (6.0% unchanged)”
Apparent clearance (CL/F), geometric mean (%CV)	“1.08 L/h (33.4%)”
Major route of elimination	“Non-enzymatic hydrolysis, followed by urinary excretion of the metabolites”
Half-life, mean, at 100 mg once daily	“60 h”
Steady-state AUC0-24 (μg•h/mL), geometric mean (%CV)	“91.8 (49.0%)”
Steady-state Cmax (μg/mL), geometric mean (%CV)	“4.62 (50.7%)”
Steady-state Ctrough (μg/mL), geometric mean (%CV)	“3.14 (50.9%)”

Basis of the values in the pharmacokinetic properties table

“The pharmacokinetic properties of pritelivir following oral administration of HOVILPRI are displayed in Table 2.” (opens the prescribing information at this quote)
“The values are based on a 100 mg once daily dose.” (opens the prescribing information at this quote)
“Food effect after high-fat meal: 150 calories from protein, 250 calories from carbohydrates, and 500-600 calories from fat; a total of 1000 calories with >50% calories from fat.” (opens the prescribing information at this quote)
“Derived from population pharmacokinetic model post-hoc estimates for all participants taking 20-280 mg single or multiple doses.” (opens the prescribing information at this quote)
“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. Values represent recovery of total radioactivity as a percentage of administered dose.” (opens the prescribing information at this quote)
“Pharmacokinetic parameter values based on post-hoc estimates from pritelivir population pharmacokinetic model in immunocompromised participants receiving 100 mg of pritelivir once daily with or without food. Geometric mean (%CV).” (opens the prescribing information at this quote)

Dose proportionality, time to steady state, and accumulation

“Cmax and AUC were dose-proportional after single dose administration (20–480 mg) and multiple dose administration (5–400 mg once daily).” (opens the prescribing information at this quote)
“After multiple dosing of 100 mg once daily, steady state was reached within 8 days.” (opens the prescribing information at this quote)
“When a loading dose of 400 mg pritelivir was administered on Day 1 followed by a maintenance dose of 100 mg once daily, steady-state exposures were reached on Day 2.” (opens the prescribing information at this quote)
“Plasma concentrations at steady state are approximately 5-fold higher than those after single dose administration.” (opens the prescribing information at this quote)

Covariates: age, sex, race, body weight, and underlying immunocompromised condition

“There were no clinically significant differences in the pharmacokinetics of pritelivir based on age (19 to 84 years), gender, race (including American Indian/Alaska Native, Asian, Black/African American, White, or other), body weight (48 to 176 kg), or underlying immunocompromised condition (including HIV/AIDS, oncology, transplant, or autoimmune/inflammatory disorder).” (opens the prescribing information at this quote)

First-in-human trials: design, linearity, half-life, and time to steady state

“The pharmacokinetics and safety of the novel herpes simplex virus helicase-primase inhibitor pritelivir were evaluated in 5 phase 1 trials: a single-ascending-dose trial, 2 multiple-ascending-dose trials, a food-effect trial, and an absolute bioavailability trial in healthy male subjects.” (opens the source at this quote in a new tab)
“One cohort of healthy female subjects was included in the single-ascending-dose trial.” (opens the source at this quote in a new tab)
“Pritelivir pharmacokinetics were linear up to 480 mg following single and up to 400 mg following multiple once-daily doses.” (opens the source at this quote in a new tab)
“The half-life ranged from 52 to 83 hours, and steady state was reached between 8 and 13 days.” (opens the source at this quote in a new tab)

First-in-human trials: sex, absolute bioavailability, and food effect

“Maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration were 1.5- and 1.1-fold higher in female compared to male subjects.” (opens the source at this quote in a new tab)
“Absolute bioavailability was 72% under fasted conditions.” (opens the source at this quote in a new tab)
“Following a fatty diet, pritelivir time to maximum concentration was 1.5 hour delayed and maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration were 33% and 16% higher, respectively.” (opens the source at this quote in a new tab)

Clearance, volume of distribution, and protein binding reported from the phase 1 trials

“Absolute bioavailability was 72% under fasted conditions, and mean clearance (CL) and volume of distribution (Vd) were estimated to be 0.82 L/h and 79 L, respectively.” (opens the source at this quote in a new tab)
“In vitro plasma protein binding of pritelivir was high, with a mean fraction unbound of about 2.8% in humans. It was not concentration dependent, and binding was mainly to albumin.” (opens the source at this quote in a new tab)
“It should be noted that the ex vivo results on the free fraction in these trials (ie, 0.607% and 0.551% for the control groups in the renal and hepatic impairment trials, respectively) were different from earlier in vitro results, as mentioned previously (2.8%).” (opens the source at this quote in a new tab)
“This can be explained by the different methods that were used throughout development.” (opens the source at this quote in a new tab)

Median time to maximum concentration under fasted conditions

“Absolute bioavailability was 72% under fasted conditions with a median tmax at 3.5 hours after dosing.” (opens the source at this quote in a new tab)

Sex and body weight: steady-state exposure in two interaction trials

“A 23% higher AUC0-24 h was observed in females compared to males. 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)

Mass balance trials: design

“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)
“Blood, urine, and feces samples were collected up to 26 days postdose.” (opens the source at this quote in a new tab)
“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)
“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)

Mass balance trials: recovery and routes of excretion

“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)
“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)
“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)
“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)
“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)

Mass balance trials: metabolic pathways

“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)
“Furthermore, in human hepatocytes, roughly half of the loss of parent drug in suspended human hepatocytes was attributed to nonenzymatic amide hydrolysis, which was observed in the human mass balance studies.” (opens the source at this quote in a new tab)

“The metabolites PPA and ATS were tested to be pharmacologically inactive on HSV replication.” (opens the source at this quote in a new tab)

Mass balance trials: components in plasma as stated in the abstract

“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)

Mass balance trials: components in plasma as stated in the results

“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)
“Based on the metabolic profiling results of both trials, 3 metabolites were detected in plasma, of which PPA was identified as the main metabolite (10.1% of TRA) and ATS (5.9%) and hydroxylated pritelivir (1.9%) as minor metabolites.” (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)

Mass balance trials: components in urine and feces

“The main components in urine were PPA-acyl glucuronide (and its isomers), ATS, and its N-demethylated isomers.” (opens the source at this quote in a new tab)
“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)
“Pritelivir accounted for 0.9% (0.6% of the administered dose).” (opens the source at this quote in a new tab)
“Only minor metabolites were observed in feces.” (opens the source at this quote in a new tab)
“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)
“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)

Steady-state pharmacokinetic parameters in the multiple-dose mass balance trial

Parameter, mean (SD) unless stated	Pritelivir, day 8
Cmax,ss (ng/mL)	“5889 (1924)”
Cmin (ng/mL)	“3194 (739.1)”
tmax (h), median (range)	“3.00 (0.75-5.00)”
AUCtau (ng/h/mL)	“102,941 (25170)”
t1/2z (h)	“63.06 (1.904)”
CL/F (L/h)	“1.022 (0.2434)”

Distribution into red blood cells after a single dose

“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)
“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)

Pharmacokinetics in animal species and comparison with humans

“Oral bioavailability of pritelivir was 65, 83, and 63% in rat, dog, and monkey, respectively. The drug was eliminated with half-lives of 5–10 h in rodents, 22–39 h in dogs, and 30 h in monkeys.” (opens the source at this quote in a new tab)
“In vitro experiments in microsomes and hepatocytes confirmed that cytochrome P450-dependent metabolism is not the major route of metabolic clearance of pritelivir.” (opens the source at this quote in a new tab)

Exposure relative to effective concentrations in a murine infection model

“The administration of pritelivir at 10 mg/kg of body weight once daily for 4 days completely suppressed any signs of HSV infection in the animals.” (opens the source at this quote in a new tab)
“Associated plasma concentrations adjusted for protein binding stayed above the cell culture 90% effective concentration” (opens the source at this quote in a new tab)