Mass Balance and Metabolite Profile after Single and Multiple Oral Doses of Pritelivir in Healthy Subjects.

Pritelivir is a helicase-primase inhibitor active against HSV. 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. Blood, urine, and feces samples were collected up to 26 days postdose. The plasma half-life of pritelivir was 63-67 hours. Overall, 92% and 66% of the administered dose was recovered in the multiple and single dose trials, respectively. The low recovery after the single dose (66%) was most likely related to the formulation used. The major metabolic pathway was amide hydrolysis leading to amino thiazole sulfonamide (ATS) and pyridinyl phenyl acetic acid (PPA). In plasma, pritelivir, ATS, PPA, and PPA-acyl glucuronide accounted for 40.6%, 9.4%, 5.1%, and 0.2% of total radioactivity. More than 90% of drug-related material was eliminated 624 hours postdose. The majority was excreted in urine (75% and 77%), followed by feces (16% and 23%). The main components in urine were PPA-acyl glucuronide (and its isomers), ATS, and its N-demethylated isomers. Only minor metabolites were observed in feces. In conclusion, the major metabolic pathways of pritelivir have been identified with the primary excretion route being renal.

First-in-Human, Single- and Multiple-Ascending-Dose, Food-Effect, and Absolute Bioavailability Trials to Assess the Pharmacokinetics, Safety, and Tolerability of Pritelivir, a Nonnucleoside Helicase-Primase Inhibitor Against Herpes Simplex Virus in Healthy Subjects.

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. One cohort of healthy female subjects was included in the single-ascending-dose trial. Pritelivir pharmacokinetics were linear up to 480 mg following single and up to 400 mg following multiple once-daily doses. The half-life ranged from 52 to 83 hours, and steady state was reached between 8 and 13 days. 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. Absolute bioavailability was 72% under fasted conditions. 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. Pritelivir was safe and well tolerated up to 600 mg following single and up to 200 mg following multiple once-daily doses. 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.

Discovery, Chemistry, and Preclinical Development of Pritelivir, a Novel Treatment Option for Acyclovir-Resistant Herpes Simplex Virus Infections.

When the nucleoside analogue acyclovir was introduced in the early 1980s, it presented a game-changing treatment modality for herpes simplex virus infections. Since then, work has been ongoing to improve the weaknesses that have now been identified: a narrow time window for therapeutic success, resistance in immunocompromised patients, little influence on frequency of recurrences, relatively fast elimination, and poor bioavailability. The present Drug Annotation focuses on the helicase-primase inhibitor pritelivir currently in development for the treatment of acyclovir-resistant HSV infections and describes how a change of the molecular target (from viral DNA polymerase to the HSV helicase-primase complex) afforded improvement of the shortcomings of nucleoside analogs. Details are presented for the discovery process leading to the final drug candidate, the pivotal preclinical studies on mechanism of action and efficacy, and on how ongoing clinical research has been able to translate preclinical promises into clinical use.

The Effect of Oral Letermovir Administration on the Pharmacokinetics of a Single Oral Dose of P-Glycoprotein Substrate Digoxin in Healthy Volunteers.

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor approved in the United States, Canada, Japan, and the European Union for prophylaxis of CMV infection and disease in CMV-seropositive, allogeneic, hematopoietic stem-cell transplant recipients. In vitro, letermovir is a substrate and potential modulator of P-glycoprotein. The potential of letermovir to alter the pharmacokinetics of digoxin (a P-glycoprotein substrate) upon coadministration in healthy subjects was therefore investigated in a phase 1 trial (EudraCT: 2011-004516-39). Oral letermovir 240 mg was administered twice daily for 12 days with a single oral digoxin 0.5-mg dose on day 7; after a washout period, oral digoxin 0.5 mg was administered on day 35 (sequence 1). The period order was reversed after a 28-day washout for sequence 2. Pharmacokinetics and safety were evaluated. The presence of steady-state letermovir reduced digoxin area under the plasma concentration-time curve from administration until last quantifiable measurement by 12% and maximum plasma concentration by 22% compared with digoxin alone; digoxin half-life and elimination rate remained similar in both conditions. The between-subject variability of digoxin maximum plasma concentration was higher with letermovir than without (42% vs 31%) and similar for digoxin area under the plasma concentration-time curve in both periods. No specific safety or tolerability concerns were identified. Overall, letermovir had no clinically relevant effect on concomitant administration with digoxin.

Pharmacokinetics and Safety of Letermovir and Midazolam Coadministration in Healthy Subjects.

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection and disease in allogeneic hematopoietic stem-cell transplant recipients. In vitro studies have identified letermovir as a potential cytochrome P450 (CYP) 3A inhibitor. Thus, the effect of letermovir on the CYP3A isoenzyme-specific probe drug midazolam was investigated in a phase 1 trial. Healthy female subjects received single-dose intravenous (IV; 1 mg) and oral (2 mg) midazolam on days -4 and -2, respectively. Letermovir 240 mg once daily was administered on days 1 to 6, and further single doses of midazolam 1 mg IV and oral midazolam 2 mg were administered on days 4 and 6, respectively. Pharmacokinetics, tolerability, and safety were monitored throughout the trial. Following coadministration with letermovir, the least square means ratio for maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last measurable concentration was 172.4% and 225.3%, respectively, for oral midazolam, and 105.2% and 146.6%, respectively, for midazolam IV. The area under the plasma concentration-time curve from time 0 to the last measurable concentration ratio of midazolam to 1-hydroxymidazolam increased slightly in the presence of letermovir following IV (8.8-13.1; 49% increase) and oral (3.3-5.3; 59% increase) midazolam. Letermovir reached steady state, on average, by days 5 to 6. All treatments were generally well tolerated. Letermovir demonstrated moderate CYP3A inhibition.

Absorption, Metabolism, Distribution, and Excretion of Letermovir.

BACKGROUND: Letermovir is approved for prophylaxis of cytomegalovirus infection and disease in cytomegalovirus-seropositive hematopoietic stem-cell transplant (HSCT) recipients. OBJECTIVE: HSCT recipients are required to take many drugs concomitantly. The pharmacokinetics, absorption, distribution, metabolism, and excretion of letermovir and its potential to inhibit metabolizing enzymes and transporters in vitro were investigated to inform on the potential for drug-drug interactions (DDIs). METHODS: A combination of in vitro and in vivo studies described the absorption, distribution, metabolism, and routes of elimination of letermovir, as well as the enzymes and transporters involved in these processes. The effect of letermovir to inhibit and induce metabolizing enzymes and transporters was evaluated in vitro and its victim and perpetrator DDI potentials were predicted by applying the regulatory guidance for DDI assessment. RESULTS: Letermovir was a substrate of CYP3A4/5 and UGT1A1/3 in vitro. Letermovir showed concentration- dependent uptake into organic anionic transporting polypeptide (OATP)1B1/3-transfected cells and was a substrate of P-glycoprotein (P-gp). In a human ADME study, letermovir was primarily recovered as unchanged drug and minor amounts of a direct glucuronide in feces. Based on the metabolic pathway profiling of letermovir, there were few oxidative metabolites in human matrix. Letermovir inhibited CYP2B6, CYP2C8, CYP3A, and UGT1A1 in vitro, and induced CYP3A4 and CYP2B6 in hepatocytes. Letermovir also inhibited OATP1B1/3, OATP2B1, OAT3, OCT2, BCRP, BSEP, and P-gp. CONCLUSION: The body of work presented in this manuscript informed on the potential for DDIs when letermovir is administered both intravenously and orally in HSCT recipients.

Pharmacokinetics and Safety of Letermovir Coadministered With Cyclosporine A or Tacrolimus in Healthy Subjects.

Letermovir is being developed for human cytomegalovirus infection treatment and prophylaxis. In patients receiving transplants, antivirals are coadministered with cyclosporine A (CsA) or tacrolimus (TAC) immunosuppressants. Therefore, we investigated the potential for letermovir-immunosuppressant interactions. In 2 phase 1 clinical trials either CsA 50 mg or TAC 5 mg was administered to healthy males. Following washout, letermovir 80 mg was dosed twice daily for 7 and 11 days in the CsA and TAC trials, respectively, with a second dose of immunosuppressant coadministered with letermovir at steady state. In addition, letermovir 40 mg twice daily was administered for 14 days, and either CsA 50 or 200 mg administered on days 7 and 14. Pharmacokinetics and tolerability were assessed. Letermovir increased CsA and TAC Cmax by 37% and 70%, respectively, and exposure by 70% and 78%, respectively, compared with immunosuppressant alone; t½ was also increased from 10.7 to 17.9 hours for CsA. CsA (50/200 mg) increased letermovir Cmax,ss (109%/167%) and AUCss,τ (126%/237%) and decreased t½ (4.33 to 3.68/3.04 hours) versus letermovir alone. TAC did not significantly affect letermovir pharmacokinetics. All treatments were well tolerated. Concomitant letermovir increased TAC and CsA exposure. CsA altered letermovir pharmacokinetics, whereas TAC did not.

Pharmacokinetics and safety of the anti-human cytomegalovirus drug letermovir in subjects with hepatic impairment.

AIMS: Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on letermovir pharmacokinetics. METHODS: Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral letermovir in female subjects with hepatic impairment and healthy matched controls. For 8 days, subjects with moderate hepatic impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg letermovir/day and those with severe hepatic impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg letermovir/day. Pharmacokinetic parameters were determined from blood samples. RESULTS: For subjects with moderate hepatic impairment, maximal observed concentration at steady state (Css,max ) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,ss ) for total letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, Css,max and AUCτ,ss values of total letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. CONCLUSIONS: Moderate hepatic impairment increased exposure to letermovir <2-fold, while severe hepatic impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment.

Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment.

AIMS: Human cytomegalovirus remains a significant issue for immunocompromised patients and existing viral polymerase targeting therapies are associated with significant toxicity. Accordingly, the viral terminase complex inhibitor, letermovir, is in development. We assessed letermovir pharmacokinetics in renal impairment. METHODS: This was a Phase 1, open-label, nonrandomised trial. Estimated glomerular filtration rate based on the Modification of Diet Renal Disease equation was used to create three groups of eight subjects: healthy function (estimated glomerular filtration rate ≥ 90 ml min-1  1.73m-2 ), moderate (30-59 ml min-1  1.73m-2 ) and severe (<30 ml min-1  1.73m-2 ) impairment. Oral letermovir 120 mg was dosed once-daily for 8 days and blood collected for pharmacokinetic analyses. RESULTS: All 24 subjects enrolled completed the trial. Moderate and severe renal impairment increased mean unbound letermovir fractions by 11% and 26%, respectively, vs. healthy subjects. Exposure (AUCτ,ss and Css,max ) was increased with renal impairment [least square mean ratios (90% confidence intervals) total letermovir vs. healthy subjects, AUCτ,ss 192% (143-258%) and 142% (83-243%) for moderate and severe impairment, respectively; Css,max 125% (87-182%) and 106% (75-151%), respectively]. Clearance was decreased vs. healthy subjects. Correlation analyses indicated a correlation between decreasing renal function and increased unbound letermovir concentration (R2  = 0.5076, P < 0.0001). Correlations were identified between decreased clearance with both decreased renal function (R2  = 0.0662, P = 0.2249 and R2  = 0.1861, P = 0.0353 total and unbound clearance, respectively) and increased age (R2  = 0.3548, P = 0.0021 and R2  = 0.3166, P = 0.0042 total and unbound clearance, respectively). Multiple-dose letermovir 120 mg was well tolerated across groups. CONCLUSIONS: Renal impairment increased exposure to letermovir, although age was a confounding factor.

Pharmacokinetics-pharmacodynamics of the helicase-primase inhibitor pritelivir following treatment of wild-type or pritelivir-resistant virus infection in a murine herpes simplex virus 1 infection model.

Herpes simplex virus (HSV) infections can cause considerable morbidity. Transmission of HSV-2 has become a major health concern, since it has been shown to promote transmission of other sexually transmitted diseases. Pritelivir (AIC316, BAY 57-1293) belongs to a new class of HSV antiviral compounds, the helicase-primase inhibitors, which have a mode of action that is distinct from that of antiviral nucleoside analogues currently in clinical use. Analysis of pharmacokinetic-pharmacodynamic parameters is a useful tool for the selection of appropriate doses in clinical trials, especially for compounds belonging to new classes for which no or only limited data on therapeutic profiles are available. For this purpose, the effective dose of pritelivir was determined in a comprehensive mouse model of HSV infection. Corresponding plasma concentrations were measured, and exposures were compared with efficacious concentrations derived from cell cultures. 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. Associated plasma concentrations adjusted for protein binding stayed above the cell culture 90% effective concentration (EC90) for HSV-1 for almost the entire dosing interval. Interestingly, by increasing the dose 6-fold and prolonging the treatment duration to 8 days, it was possible to treat mice infected with an approximately 30-fold pritelivir-resistant but fully pathogenic HSV-1 virus. Corresponding plasma concentrations exceeded the EC90 of this mutant for <8 h, indicating that even suboptimal exposure to pritelivir is sufficient to achieve antiviral efficacy, possibly augmented by other factors such as the immune system.