A drug-drug interaction study with letermovir and acyclovir in healthy participants.

Letermovir inhibits renal tubular organic anion transporter 3 (OAT3) in vitro and is predicted to inhibit OAT3 in vivo. Acyclovir, a substrate for OAT3, is likely to be coadministered with letermovir; therefore, letermovir may increase acyclovir concentrations. A drug-drug interaction study was conducted in healthy participants (N = 16) to assess the effect of letermovir on acyclovir pharmacokinetics. On Day 1, participants received a single oral dose of 400 mg acyclovir; on Days 2-7, participants received oral doses of 480 mg letermovir once daily with a single oral dose of 400 mg acyclovir coadministered on Day 7. Coadministration with letermovir resulted in geometric mean ratios (90% confidence intervals) for acyclovir area under the concentration-time curve from administration to infinity and maximum plasma concentration of 1.02 (0.87-1.20) and 0.82 (0.71-0.93), respectively. No notable safety issues were reported. No clinically significant interaction was observed between letermovir and acyclovir in healthy participants and no dose adjustment is required for coadministration.

Evaluation of the inhibitory effects of itraconazole on letermovir.

AIMS: Letermovir, a cytomegalovirus (CMV) DNA terminase complex inhibitor, is a substrate of ABCB1 (P-glycoprotein; P-gp), organic anion transporting polypeptide (OATP)1B1/3, UDP-glucuronosyltransferase (UGT)1A1, UGT1A3 and possibly ABCG2 (breast cancer resistance protein; BCRP). A study was conducted to evaluate the effects of itraconazole, a prototypic ABCB1/ABCG2 inhibitor, on letermovir pharmacokinetics (PK) and the effects of letermovir on itraconazole PK. METHODS: In an open-label, fixed-sequence study in 14 healthy participants, 200 mg oral itraconazole was administered once daily for 4 days. Following a 10-day washout, 480 mg oral letermovir was administered once daily for 14 days (Days 1-14) and then coadministered with 200 mg itraconazole once daily for 4 days (Days 15-18). Intensive PK sampling was performed for letermovir and itraconazole. PK and safety were evaluated. RESULTS: Letermovir geometric mean ratio (GMR; 90% confidence interval [CI]) for area under the concentration-time curve from time 0 to 24 h (AUC0-24 ) was 1.33 (1.17, 1.51) and for maximum concentration (Cmax ) was 1.21 (1.05, 1.39) following administration with/without itraconazole. Itraconazole GMR (90% CI) for AUC0-24 was 0.76 (0.71, 0.81) and for Cmax was 0.84 (0.76, 0.92) following administration with/without letermovir. Coadministration of letermovir with itraconazole was generally well tolerated. CONCLUSIONS: The increase in letermovir exposure with coadministration of itraconazole is likely predominantly due to inhibition of intestinal ABCB1 and potentially ABCG2 transport. The mechanism for the decrease in itraconazole exposure is unknown. The modest changes in letermovir and itraconazole PK are not considered clinically meaningful.

Reaction Phenotyping of Low-Turnover Compounds in Long-Term Hepatocyte Cultures Through Persistent Selective Inhibition of Cytochromes P450.

Recognizing the challenges of determining the relative contribution of different drug metabolizing enzymes to the metabolism of slowly metabolized compounds, a cytochrome P450 reaction phenotyping (CRP) method using cocultured human hepatocytes (HEPATOPAC) has been established. In this study, the emphasis on the relative contribution of different cytochrome P450 (P450) isoforms was assessed by persistently inhibiting P450 isoforms over 7 days with human HEPATOPAC. P450 isoform-selective inhibition was achieved with the chemical inhibitors furafylline (CYP1A2), tienilic acid (CYP2C9), (+)-N-3-benzylnirvanol (CYP2C19), paroxetine (CYP2D6), azamulin (CYP3A), and a combination of 1-aminobenzotriazole and tienilic acid (broad spectrum inhibition of P450s). We executed this CRP method using HEPATOPAC by optimizing for the choice of P450 inhibitors, their selectivity, and the temporal effect of inhibitor concentrations on maintaining selectivity of inhibition. In general, the established CRP method using potent and selective chemical inhibitors allows to measure the relative contribution of P450s and to calculate the fraction of metabolism (f m) of low-turnover compounds. Several low-turnover compounds were used to validate this CRP method by determining their hepatic intrinsic clearance and f m, with comparison with literature values. We established the foundation of a robust CRP for low-turnover compound test system which can be expanded to include inhibition of other drug metabolizing enzymes. This generic CRP assay, using human long-term hepatocyte cultures, will be an essential tool in drug development for new chemical entities in the quantitative assessment of the risk as a victim of drug-drug interactions. SIGNIFICANCE STATEMENT: An ongoing trend is to develop drug candidates which have limited metabolic clearance. The current studies report a generic approach to conducting reaction phenotyping studies with human HEPATOPAC, focusing on P450 metabolism of low-turnover compounds. Potent and selective chemical inhibitors were used to assess the relative contribution of the major human P450s. Validation was achieved by confirming hepatic intrinsic clearance and fraction of metabolism for previously reported low-turnover compounds. This approach is adaptable for assessment of all drug metabolizing enzymes.

Prediction of Fraction Unbound in Microsomal and Hepatocyte Incubations: A Comparison of Methods across Industry Datasets.

The fraction unbound in the incubation, fu,inc, is an important parameter to consider in the evaluation of intrinsic clearance measurements performed in vitro in hepatocytes or microsomes. Reliable estimates of fu,inc based on a compound's structure have the potential to positively impact the screening timelines in drug discovery. Previous works suggested that fu,inc is primarily driven by passive processes and can be described using physicochemical properties such as lipophilicity and the protonation state of the molecule. While models based on these principles proved predictive in relatively small datasets that included marketed drugs, their applicability domain has not been extensively explored. The work presented here from the in silico ADME discussion group (part of the International Consortium for Innovation through Quality in Pharmaceutical Development, the IQ consortium) describes the accuracy of these models in large proprietary datasets that include several thousand of compounds across chemical space. Overall, the models do well for compounds with low lipophilicity. In other words, the equations correctly predict that fu,inc is, in general, above 0.5 for compounds with a calculated logP of less than 3. When applied to lipophilic compounds, the models failed to produce quantitatively accurate predictions of fu,inc, with a high risk of underestimating binding properties. These models can, therefore, be used quantitatively for less lipophilic compounds. On the other hand, internal machine-learning models using a company's own proprietary dataset also predict compounds with higher lipophilicity reasonably well. Additionally, the data shown indicate that microsomal binding is, in general, a good proxy for hepatocyte binding.

Novel oxazolidinone calcitonin gene-related peptide (CGRP) receptor antagonists for the acute treatment of migraine.

In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 µM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).

siRNA-mediated knockdown of P450 oxidoreductase in rats: a tool to reduce metabolism by CYPs and increase exposure of high clearance compounds.

PURPOSE: To develop a tool based on siRNA-mediated knockdown of hepatic P450 oxidoreductase (POR) to decrease the CYP-mediated metabolism of small molecule drugs that suffer from rapid metabolism in vivo, with the aim of improving plasma exposure of these drugs. METHODS: siRNA against the POR gene was delivered using lipid nanoparticles (LNPs) into rats. The time course of POR mRNA knockdown, POR protein knockdown, and loss of POR enzyme activity was monitored. The rat livers were harvested to produce microsomes to determine the impact of POR knockdown on the metabolism of several probe substrates. Midazolam (a CYP3A substrate with high intrinsic clearance) was administered into LNP-treated rats to determine the impact of POR knockdown on midazolam pharmacokinetics. RESULTS: Hepatic POR mRNA and protein levels were significantly reduced by administering siRNA and the maximum POR enzyme activity reduction (~85%) occurred 2 weeks post-dose. In vitro analysis showed significant reductions in metabolism of probe substrates due to POR knockdown in liver, and in vivo POR knockdown resulted in greater than 10-fold increases in midazolam plasma concentrations following oral dosing. CONCLUSIONS: Anti-POR siRNA can be used to significantly reduce hepatic metabolism by various CYPs as well as greatly increase the bioavailability of high clearance compounds following an oral dose, thus enabling it to be used as a tool to increase drug exposure in vivo.

Pharmacokinetics, Safety, and Efficacy of Letermovir for Cytomegalovirus Prophylaxis in Adolescent Hematopoietic Cell Transplantation Recipients.

INTRODUCTION: Letermovir is a cytomegalovirus (CMV) terminase complex inhibitor approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic cell transplantation (allo-HCT) recipients (R+). We report pharmacokinetics (PK), safety, and efficacy of letermovir in adolescent (12-18 years) allogeneic HCT recipients from an ongoing clinical study. METHODS: In this phase 2b, multicenter, open-label study (NCT03940586), 28 adolescents received 480 mg letermovir [240 mg with cyclosporin A (CsA)] once daily orally or intravenously. Blood was collected for intensive (n = 14) plasma concentrations of letermovir. Intensive PK data were used for dose confirmation. Target exposure range 34,400-100,000 h × ng/mL for pediatric median exposures was based on model-predicted phase 3 population PK simulations in adult HCT recipients. RESULTS: All participants were CMV-seropositive (body weight 28.7-95.0 kg). Of 12 PK-evaluable participants, 8 receiving 480 mg letermovir without CsA and 4 receiving 240 mg letermovir with CsA achieved exposures comparable to the adult exposure range. Exposure above the target but below the adult clinical program maximum was observed in 1 patient. Safety was consistent with previously described safety in adults. The proportion of participants with clinically significant CMV infection through week 24 post-HCT was comparable (24%) to that in the pivotal phase 3 study in adults (37.5%). CONCLUSIONS: Administration of adult letermovir doses in this adolescent cohort resulted in exposures within adult clinical program margins and was associated with safety and efficacy similar to adults. Results support a letermovir dose of 480 mg (240 mg with CsA) in adolescent allo-HCT recipients.

Inhibin B response to testicular toxicants hexachlorophene, ethane dimethane sulfonate, di-(n-butyl)-phthalate, nitrofurazone, DL-ethionine, 17-alpha ethinylestradiol, 2,5-hexanedione, or carbendazim following short-term dosing in male rats.

BACKGROUND: Inhibin B is a heterodimer glycoprotein that downregulates follicle-stimulating hormone and is produced predominantly by Sertoli cells. The potential correlation between changes in plasma Inhibin B and Sertoli cell toxicity was evaluated in male rats administered testicular toxicants in eight studies. Inhibin B fluctuations over 24 hr were also measured. METHODS: Adult rats were administered one of eight testicular toxicants for 1 to 29 days. The toxicants were DL-ethionine, dibutyl phthalate, nitrofurazone, 2,5-hexanedione, 17-alpha ethinylestradiol, ethane dimethane sulfonate, hexachlorophene, and carbendazim. In a separate study plasma was collected throughout a 24-hr period via an automatic blood sampler. RESULTS: Histomorphologic testicular findings included seminiferous tubule degeneration, round and elongate spermatid degeneration/necrosis, seminiferous tubule vacuolation, aspermatogenesis, and interstitial cell degeneration. There was a varying response of plasma Inhibin B levels to seminiferous tubule toxicity, with three studies showing high correlation, three studies with a response only at a certain time or dose, and two studies with no Inhibin B changes. In a receiver operating characteristics exclusion model analysis, where treated samples without histopathology were excluded, Inhibin B showed a sensitivity of 70% at 90% specificity in studies targeting seminiferous tubule toxicity. CONCLUSION: Decreases in Inhibin B correlated with Sertoli cell toxicity in the majority of studies evaluated, demonstrating the value of Inhibin B as a potential biomarker of testicular toxicity. There was no correlation between decreases in Inhibin B and interstitial cell degeneration. In addition, a pattern of Inhibin B secretion could not be identified over 24 hr.

Developing a mechanistic understanding of the nonlinear pharmacokinetics of letermovir and prospective drug interaction with everolimus using physiological-based pharmacokinetic modeling.

Letermovir is approved for use in cytomegalovirus-seropositive hematopoietic stem cell transplant recipients and is investigated in other transplant settings. Nonlinear pharmacokinetics (PKs) were observed in clinical studies after intravenous and oral dosing across a wide dose range, including the efficacious doses of 240 and 480 mg. A physiologically-based PK (PBPK) model for letermovir was built to develop a plausible explanation for the nonlinear PKs observed in clinical studies. In vitro studies suggested that letermovir elimination and distribution are mediated by saturable uridine glucuronosyltransferases (UGT)-metabolism and by saturable hepatic uptake via organic anion-transporting polypeptides (OATP) 1B. A sensitivity analysis of parameters describing the metabolism and distribution mechanisms indicated that the greater than dose-proportional increase in letermovir exposure is best described by a saturable OATP1B-mediated transport. This PBPK model was further used to evaluate the drug interaction potential between letermovir and everolimus, an immunosuppressant that may be co-administered with letermovir depending on regions. Because letermovir inhibits cytochrome P450 (CYP) 3A and everolimus is a known CYP3A substrate, an interaction when concomitantly administered is anticipated. The drug-drug interaction simulation confirmed that letermovir will likely increase everolimus are under the curve by 2.5-fold, consistent with the moderate increase in exposure observed with midazolam in the clinic. The output highlights the importance of drug monitoring, which is common clinical practice for everolimus to maintain safe and efficacious drug concentrations in the targeted patient population when concomitantly administered with letermovir.

Acute and Chronic Effects of Rifampin on Letermovir Suggest Transporter Inhibition and Induction Contribute to Letermovir Pharmacokinetics.

Rifampin has acute inhibitory and chronic inductive effects that can cause complex drug-drug interactions. Rifampin inhibits transporters including organic-anion-transporting polypeptide (OATP)1B and P-glycoprotein (P-gp), and induces enzymes and transporters including cytochrome P450 3A, UDP-glucuronosyltransferase (UGT)1A, and P-gp. This study aimed to separate inhibitory and inductive effects of rifampin on letermovir disposition and elimination (indicated for cytomegalovirus prophylaxis in hematopoietic stem cell transplant recipients). Letermovir is a substrate of UGT1A1/3, P-gp, and OATP1B, with its clearance primarily mediated by OATP1B. Letermovir (single-dose) administered with rifampin (single-dose) resulted in increased letermovir exposure through transporter inhibition. Chronic coadministration with rifampin (inhibition plus potential OATP1B induction) resulted in modestly decreased letermovir exposure vs. letermovir alone. Letermovir administered 24 hours after the last rifampin dose (potential OATP1B induction) resulted in markedly decreased letermovir exposure. These data suggest rifampin may induce transporters that clear letermovir; the modestly reduced letermovir exposure with chronic rifampin coadministration likely reflects the net effect of inhibition and induction. OATP1B endogenous biomarkers coproporphyrin (CP) I and glycochenodeoxycholic acid-sulfate (GCDCA-S) were also analyzed; their exposures increased after single-dose rifampin plus letermovir, consistent with OATP1B inhibition and prior reports of inhibition by rifampin alone. CP I and GCDCA-S exposures were substantially reduced with letermovir administered 24 hours after the last dose of rifampin vs. letermovir plus chronic rifampin coadministration. This study suggests that OATP1B induction may contribute to reduced letermovir exposure after chronic rifampin administration, although given the complexity of letermovir disposition alternative mechanisms are not fully excluded.

Drug-Drug Interaction of Letermovir and Atorvastatin in Healthy Participants.

Letermovir (MK-8228/AIC246) is a cytomegalovirus (CMV) DNA terminase complex inhibitor for CMV prophylaxis in adult patients undergoing hematopoietic stem cell transplant. It is cytochrome P450 (CYP) 3A inhibitor and inhibits organic anion transporting polypeptide 1B1/3 and breast cancer resistance protein transporters. Atorvastatin (ATV), a commonly used treatment for hypercholesterolemia, is a substrate of organic anion transporting polypeptide 1B1, potentially breast cancer resistance protein, and CYP3A. As letermovir may be coadministered with ATV, the effect of multiple-dose letermovir 480 mg once daily on the pharmacokinetics of single-dose ATV 20 mg and its metabolites (ortho-hydroxyatorvastatin [o-OH-ATV] and para-hydroxyatorvastatin [p-OH-ATV]) was evaluated in an open-label trial in healthy female adults (N = 14). ATV area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration (Cmax ) increased ≈3-fold with letermovir coadministration. The time to ATV Cmax also increased, while apparent clearance decreased. The exposures of o-OH-ATV and p-OH-ATV were comparable in the presence versus absence of letermovir; however, o-OH-ATV Cmax decreased by 60% with coadministration, while p-OH-ATV Cmax was similar. Due to the increase in ATV exposure with letermovir coadministration, statin-associated adverse events such as myopathy should be closely monitored following coadministration. The dose of ATV should not exceed 20 mg daily when coadministered with letermovir.

Novel cytochrome P450-mediated ring opening of the 1,3,4-oxadiazole in setileuton, a 5-lipoxygenase inhibitor.

Setileuton [4-(4-fluorophenyl)-7-[({5-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-1-benzopyran-2-one] is a selective inhibitor of the 5-lipoxygenase enzyme, which is under investigation for the treatment of asthma and atherosclerosis. During the development of setileuton, a metabolite (M5) was identified in incubations with rat, dog, and human liver microsomes that represented the addition of 18 Da to the 1,3,4-oxadiazole portion of the molecule. Based on mass spectral data, a ring opened structure was proposed and confirmed through comparison with a synthetic standard. The metabolic ring opening was examined in vitro in rat liver microsomes and was determined to be mediated by cytochrome P450s (P450s). Upon examination of the specific P450s involved using cDNA-expressed rat P450s, it was shown that CYP1A2 likely was the major isoform contributing to the formation of M5. Studies using stable labeled molecular oxygen and water demonstrated that the oxygen was incorporated from molecular oxygen, rather than water, and confirmed that the metabolic formation was oxidative. An alternative, comparatively slow pathway of chemical hydrolysis also was identified and described. Three potential mechanisms for the two-step metabolic ring opening of the 1,3,4-oxadizole are proposed.

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.

Assessment of Pharmacokinetic Interaction Between Letermovir and Fluconazole in Healthy Participants.

Letermovir is a prophylactic agent for cytomegalovirus infection and disease in adult cytomegalovirus-seropositive recipients of allogeneic hematopoietic stem cell transplant. As the antifungal agent fluconazole is administered frequently in transplant recipients, a drug-drug interaction study was conducted between oral letermovir and oral fluconazole. A phase 1 open-label, fixed-sequence study was performed in healthy females (N = 14, 19-55 years). In Period 1, a single dose of fluconazole 400 mg was administered. Following a 14-day washout, a single dose of letermovir 480 mg was administered (Period 2), and after a 7-day washout, single doses of fluconazole 400 mg and letermovir 480 mg were coadministered in Period 3. Pharmacokinetics and safety were evaluated. The pharmacokinetics of fluconazole and letermovir were not meaningfully changed following coadministration. Fluconazole geometric mean ratio (GMR; 90% confidence interval [CI]) with letermovir for area under the concentration-versus-time curve from time 0 to infinity (AUC0-∞ ) was 1.03 (0.99-1.08); maximum concentration (Cmax ) was 0.95 (0.92-0.99). Letermovir AUC0-∞ GMR (90%CI) was 1.11 (1.01-1.23), and Cmax was 1.06 (0.93-1.21) following coadministration with fluconazole. Coadministration of fluconazole and letermovir was generally well tolerated.

Tricyclic imidazole antagonists of the Neuropeptide S Receptor.

A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo.

PBPK Modeling Strategy for Predicting Complex Drug Interactions of Letermovir as a Perpetrator in Support of Product Labeling.

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection in allogeneic hematopoietic stem-cell transplant (HSCT) recipients. In vitro, letermovir is a time-dependent inhibitor and an inducer of cytochrome P450 (CYP)3A, and an inhibitor of CYP2C8 and organic anion transporting polypeptide (OATP)1B. A stepwise approach was taken to qualify the interaction model of an existing letermovir physiologically based pharmacokinetic model to predict letermovir interactions with CYP3A and OATP1B. The model was then used to prospectively predict the interaction between letermovir and CYP2C8 substrates such as repaglinide, a substrate of CYP2C8, CYP3A, and OATP1B. The results showed that letermovir modestly increased the exposure of CYP2C8 substrates. These results were used to inform the US prescribing information in the absence of clinical drug-drug interaction studies. In addition, midazolam interactions with letermovir at therapeutic doses were also simulated to confirm that letermovir is a moderate CYP3A inhibitor.

Expanded Physiologically-Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction.

As rifampicin can cause the induction and inhibition of multiple metabolizing enzymes and transporters, it has been challenging to accurately predict the complex drug-drug interactions (DDIs). We previously constructed a physiologically-based pharmacokinetic (PBPK) model of rifampicin accounting for the components for the induction of cytochrome P450 (CYP) 3A/CYP2C9 and the inhibition of organic anion transporting polypeptide 1B (OATP1B). This study aimed to expand and verify the PBPK model for rifampicin by incorporating additional components for the induction of OATP1B and CYP2C8 and the inhibition of multidrug resistance protein 2. The established PBPK model was capable of accurately predicting complex rifampicin-induced alterations in the profiles of glibenclamide, repaglinide, and coproporphyrin I (an endogenous biomarker of OATP1B activities) with various dosing regimens. Our comprehensive rifampicin PBPK model may enable quantitative prediction of DDIs across diverse potential victim drugs and endogenous biomarkers handled by multiple metabolizing enzymes and transporters.

Pharmacogenetic Analysis of OATP1B1, UGT1A1, and BCRP Variants in Relation to the Pharmacokinetics of Letermovir in Previously Conducted Clinical Studies.

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is indicated for prevention of CMV infection in CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. In this analysis, functional variants in solute carrier organic anion transporter family member 1B1 (SLCO1B1), uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1), and breast cancer resistance protein (BCRP) were assessed for effects on letermovir pharmacokinetics (PK) using pooled genetic information from 296 participants in 12 phase 1 studies. Letermovir area under the plasma concentration-time curve (AUC) was increased in carriers of the SLCO1B1 variant rs4149056 C allele relative to noncarriers with a geometric mean ratio (GMR) of 1.18 (95% confidence interval [CI], 1.06-1.30) for carriers of 1 copy and 1.42 (1.10-1.84) for carriers of 2 copies of the risk allele C compared with noncarriers. The SLCO1B1 variant rs4149032 T allele was associated with a decrease in letermovir AUC with GMR (95%CI) of 0.93 (0.85-1.02) and 0.82 (0.73-0.92) for carriers of 1 and 2 copies of the risk allele T, respectively, compared with noncarriers. The UGT1A1*6 variant rs4148323 A allele was present predominantly in Asian participants and was associated with an increase in letermovir AUC compared with noncarriers (GMR, 1.36; 95%CI, 1. 1.07-1.74). SLCO1B1 variant rs2306283, UGT1A1*28 TA promoter repeat, and BCRP variant rs2231142 had no effect on letermovir PK. Together, these data suggest that variants of enzymes and transporters that are involved in the disposition of letermovir in vitro may account for some variability in letermovir PK, but do not affect exposure to a clinically relevant extent.

Pharmacokinetic Drug-Drug Interactions Between Letermovir and the Immunosuppressants Cyclosporine, Tacrolimus, Sirolimus, and Mycophenolate Mofetil.

Letermovir (AIC246, MK-8228) is a human cytomegalovirus terminase inhibitor indicated for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients that is also being investigated for use in other transplant settings. Many transplant patients receive immunosuppressant drugs, of which several have narrow therapeutic ranges. There is a potential for the coadministration of letermovir with these agents, and any potential effect on their pharmacokinetics (PK) must be understood. Five phase 1 trials were conducted in 73 healthy female participants to evaluate the effect of letermovir on the PK of cyclosporine, tacrolimus, sirolimus, and mycophenolic acid (active metabolite of mycophenolate mofetil [MMF]), as well as the effect of cyclosporine and MMF on letermovir PK. Safety and tolerability were also assessed. Coadministration of letermovir with cyclosporine, tacrolimus, and sirolimus resulted in 1.7-, 2.4-, and 3.4-fold increases in area under the plasma concentration-time curve and 1.1-, 1.6-, and 2.8-fold increases in maximum plasma concentration, respectively, of the immunosuppressants. Coadministration of letermovir and MMF had no meaningful effect on the PK of mycophenolic acid. Coadministration with cyclosporine increased letermovir area under the plasma concentration-time curve by 2.1-fold and maximum plasma concentration by 1.5-fold, while coadministration with MMF did not meaningfully affect the PK of letermovir. Given the increased exposures of cyclosporine, tacrolimus, and sirolimus, frequent monitoring of concentrations should be performed during administration and at discontinuation of letermovir, with dose adjustment as needed. These data support the reduction in clinical dosage of letermovir (to 240 mg) upon coadministration with cyclosporine.