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.

How to Interpret an Investigator's Brochure for Meaningful Risk Assessment: Results of an AGAH Discussion Forum.

PURPOSE: A discussion forum was hosted by the Association for Applied Human Pharmacology (AGAH e.V.) to critically debate how to interpret and optimise the Investigator's Brochure (IB) for meaningful risk assessment of early clinical trials. MATERIALS AND METHODS: Four topics were specifically discussed: deficiencies/uncertainties in IBs, guidance for the investigator, reference safety information, and potential risks for human subjects associated with inadequate non-clinical safety assessment in the IB. In each case, 43 participants took part in a real-time online survey with pre-defined questions to capture the audience's opinion. RESULTS: The 'Summary of Data and Guidance for the Investigator' was considered as the section of the IB with the highest need for improvement with emphasis on readability, comprehensibility, timeliness of data, and appropriateness for risk assessment. It was suggested that the IB should at least be signed by the sponsor's scientist responsible for the content on pharmacology and toxicology. It was agreed that sponsors should consider thoroughly whether changes to an IB constitute a substantial amendment, and that the IB should include a section on the change history. Non-clinical pharmacology studies with negative outcomes should be reported in the IB in order to avoid assessment bias. The reference safety information for expectedness assessment of suspected serious adverse reactions should be provided as a stand-alone section of the IB. CONCLUSION: The overall consensus was that an optimised presentation of data will ensure the best possible understanding of a compound's characteristics and an optimal benefit-risk assessment which will safeguard the participants in clinical trials.

Unintended drug exposure during pregnancy in clinical trials - a survey in early drug development.

PURPOSE: To collect information on unintended drug exposure during pregnancy in early clinical drug development. MATERIALS AND METHODS: Questionnaire mailed in autumn 2015 to members of human pharmacology societies in Europe for anonymous responses via the online tool SurveyMonkey. RESULTS: 53 of the ~ 700 addressees participated in the survey. 23 female trial participants and 11 female partners of male trial participants were exposed to investigational medicinal products during unintended pregnancies in a clinical trial. Most survey respondents confirmed adequate contraceptive methods by in/exclusion criteria and the use of pregnancy tests in female trial participants at screening and before the first dose. The last menstrual period was documented less frequently (at screening: 28 of 44, before first dose: 5 of 44 respondents). A considerable proportion of respondents denied the routine use of compliance checks about the appropriate use of contraceptive methods, had no procedures in place if contraceptive methods failed, and did not train physicians in instructing trial participants about the appropriate use of contraceptive methods. CONCLUSION: The methods to avoid unintended pregnancies during participation in a clinical trial need improvement and should include (i) pregnancy tests, (ii) documentation of last menstrual period before the first dose, (iii) compliance checks of the appropriate use of contraceptive methods, and (iv) training of trial physicians. Procedures should be in place for what to do if contraceptive methods fail.

Use of integrated clinical trial protocols - A survey in early medicines development
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PURPOSE: To collect information on the use of integrated protocols in early clinical medicines development. MATERIALS AND METHODS: The questionnaire was mailed in fall 2014 to members of human pharmacology societies in Europe for anonymous responses via the online tool SurveyMonkey®. RESULTS: 97 respondents reported on 164 integrated protocols overall. In general, integrated protocols comprised 2 or 3 trial elements. One third of integrated protocols involved patients. The most frequent trial elements were single dose, multiple dose, and food effect. Drug-drug interaction, age, gender, and relative/absolute bioavailability were less common elements. Ethnic bridging and mass balance were mentioned in single cases. Out of the entire spectrum of reported trial element combinations, single (ascending) dose plus multiple (ascending) dose was most frequent (90/164 protocols, 55%); 84% of integrated protocols used adaptive elements. 29%, 17%, and 8% of integrated protocols required 1, 2, or 3 substantial amendments, respectively. Based on 118 protocols, competent authority approval was granted to 100, deficiency letters were issued 15 times and approval was refused in 3 cases. CONCLUSION: The use of integrated protocols is common practice in early medicines development. Most often single ascending dose and multiple ascending dose were the trial elements combined in one integrated protocol. Perceived main advantages were gain in time and reduced costs. Perceived main disadvantage was increased complexity.
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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.

Who is a 'healthy subject'?-consensus results on pivotal eligibility criteria for clinical trials.

INTRODUCTION/METHODS: A discussion forum was hosted by the German not-for-profit Association for Applied Human Pharmacology (AGAH e.V.) to critically review key eligibility criteria and stopping rules for clinical trials with healthy subjects, enrolling stakeholders from the pharmaceutical industry, contract research organisations, academia, ethics committees and competent authority. RESULTS: Pivotal eligibility criteria were defined for trials with new investigational medicinal products (IMPs) or with clinically established IMPs. In general, a pulse rate ranging between 50 and 90 beats/min is recommended for first-in-human (FIH) trials, while wider ranges seem acceptable for trials with clinically established IMPs, provided there are no indications of thyroid dysfunction. Hepatic laboratory parameters not to exceed the upper limit of normal (ULN) comprise ALT (alanine aminotransferase) and AST (aspartate aminotransferase) in FIH trials, whereas slight elevations (10% above ULN) seem acceptable in trials with clinically established IMPs without known hepatotoxicity. A normal renal function is required for any clinical trial in healthy subjects. A risk-adapted approach for stopping rules was adopted. Stopping rules for an individual subject are one adverse event of severe intensity or one serious adverse event. In case of a severe adverse event, some stakeholders demand a causal relationship with the IMP (i.e. an adverse reaction). Stopping rules for a cohort are one serious adverse reaction or ≥50% of subjects experiencing any adverse reaction of moderate or severe intensity. CONSEQUENCES: The application of this consensus resulted in a reduction in protocol deficiencies issued by the competent authority.