First-in-human phase 1 trials

20 evidence topics · 3 sources

Objective

Evaluation of pharmacokinetics and safety in five phase 1 trials

“The pharmacokinetics and safety of the novel herpes simplex virus helicase-primase inhibitor pritelivir were evaluated in 5 phase 1 trials” (opens the source at this quote in a new tab)

Location and study date

No evidence found.

Study design

Types of trials reported in the publication

“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)

Trial numbers of earlier phase 1 trials named in the thorough QT trial protocol

“based on data from the first-in-human trial AIC316-01-I-01, the DDI trial AIC316-03-I-01 as well as Phase 2 trials, similar exposures can be expected in men and women in this TQT trial.” (opens the source at this quote in a new tab)
“The highest dose of 400 mg qd pritelivir (supratherapeutic dose) in the present thorough QT/QTc trial has already been investigated in male subjects in trial AIC316-01-I-05.” (opens the source at this quote in a new tab)

Eligibility criteria

Healthy women in the single-ascending-dose trial

“One cohort of healthy female subjects was included in the single-ascending-dose trial.” (opens the source at this quote in a new tab)

Sex of participants in trial AIC316-01-I-05, as stated in the thorough QT trial protocol

“It is of note that only male subjects participated in the above-mentioned trial AIC316-01-I-05” (opens the source at this quote in a new tab)

Treatment

Multiple-dose regimens of trial AIC316-01-I-05, as stated in the thorough QT trial protocol

“volunteers were treated with 200 mg once daily (21 days) or 400 mg once daily (up to 16 days)” (opens the source at this quote in a new tab)

High-fat meal composition for the food effect value in the prescribing information

“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)

Study outcomes

Rationale for using safety and pharmacokinetics as the primary endpoints

No evidence found.

Statistical analysis description

Number of participants (Planned and analyzed)

No evidence found.

Description of analysis sets

No evidence found.

Results

Participant disposition

No evidence found.

Baseline characteristics

No evidence found.

Efficacy results

Dose linearity after single and multiple doses

“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)

Half-life and time to steady state

“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)

Exposure in women compared with men

“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

“Absolute bioavailability was 72% under fasted conditions.” (opens the source at this quote in a new tab)

Food effect

“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)

Prescribing information values for absolute bioavailability, food effect, time to maximum concentration, and half-life

Parameter	Quoted value
Absolute bioavailability	“72%”
Time to maximum concentration, mean (range)	“3 h (2.0–4.5 h)”
Food effect on area under the curve	“AUC ratio fed/fasted: 1.16”
Food effect on maximum concentration	“Cmax ratio fed/fasted: 1.33”
Half-life, mean	“60 h”
Dose on which the time to maximum concentration and half-life are based	“The values are based on a 100 mg once daily dose.”

Prescribing information statements on dose proportionality and steady state

“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)
“Plasma concentrations at steady state are approximately 5-fold higher than those after single dose administration.” (opens the prescribing information at this quote)

Prescribing information statement on pharmacokinetics by sex

“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)

Sponsor summary of earlier single-dose and multiple-dose pharmacokinetics in the thorough QT trial protocol

“After single- and multiple-dose administration, there was a dose-proportional increase of the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) between 5 mg and 480 mg and in peak plasma concentration (Cmax) between 5 mg and 400 mg.” (opens the source at this quote in a new tab)
“Higher doses of pritelivir did not further increase systemic exposure, suggesting that the lack of dose proportionality may be related to capacity-limited absorption (as opposed to non-linearity in elimination).” (opens the source at this quote in a new tab)
“Further, food has no relevant effect on AUC0-last and leads only to a mild increase in Cmax.” (opens the source at this quote in a new tab)
“Moreover, the absorption from gut cannot be increased much as the absolute bioavailability is already high (>70%).” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

Not applicable.

Safety results

Tolerability by single and multiple dose

“Pritelivir was safe and well tolerated up to 600 mg following single and up to 200 mg following multiple once-daily doses.” (opens the source at this quote in a new tab)
“Considering a therapeutic dose of 100 mg once-daily, pritelivir demonstrated a favorable safety and tolerability and pharmacokinetic profile in healthy subjects to support further development.” (opens the source at this quote in a new tab)

Skin reactions at 400 mg once daily in trial AIC316-01-I-05, as stated in the thorough QT trial protocol

“pritelivir was well tolerated in the 200 mg dosing group and also well tolerated up to Day 10 in the 400 mg dosing group, however, the trial was stopped prematurely due to the occurrence of AEs belonging to the SOC skin and subcutaneous tissue disorders” (opens the source at this quote in a new tab)
“these were only observed in the 400 mg dose group” (opens the source at this quote in a new tab)
“5 of 16 subjects (4 of 12 subjects (33.3%) exposed to pritelivir, 1 of 4 subjects (25.0%) exposed to placebo) developed a macular or maculo-papular skin reaction (exanthema or eruption), mainly between Day 11 to 14 of treatment.” (opens the source at this quote in a new tab)
“These mild skin reactions were not accompanied by formation of bullae, pustules or alterations of liver function tests or eosinophilia.” (opens the source at this quote in a new tab)
“A viral infection could have been the cause but also an effect of pritelivir could not be completely ruled out.” (opens the source at this quote in a new tab)

Sponsor summary of clinical experience at supratherapeutic doses in the thorough QT trial protocol

“None of these potential risks have been observed in clinical trials with supratherapeutic doses up to 200 mg/day for 21 days or, with the exception of skin findings, up to 400 mg/day for up to 16 days.” (opens the source at this quote in a new tab)
“It remains unknown whether the skin and subcutaneous tissue disorder events were caused by pritelivir, however, if such events would occur, risk mitigation would be performed as described above.” (opens the source at this quote in a new tab)

Study limitations

Summary

The publication of the five trials is quoted from its PubMed abstract. The abstract gives no enrollment counts, trial numbers, sites, dates, or adverse event rates. Participants were healthy men, with 1 cohort of healthy women in the single-ascending-dose trial. The abstract reports tolerability up to 200 mg once daily with multiple dosing. The sponsor's thorough QT trial protocol, dated 25 November 2022, describes trial AIC316-01-I-05, which was stopped early after skin reactions in 5 of 16 participants in the 400 mg dose group (4 of 12 receiving pritelivir and 1 of 4 receiving placebo).