Maribavir, an orally available antiviral agent, has been approved in multiple countries for the treatment of patients with refractory post‐transplant cytomegalovirus (CMV) infection and/or disease. ...Maribavir is primarily metabolized by CYP3A4; coadministration with CYP3A4 inducers and inhibitors may significantly alter maribavir exposure, thereby affecting its efficacy and safety. The effect of CYP3A4 inducers and inhibitors on maribavir exposure was evaluated based on a drug‐drug interaction (DDI) study and physiologically‐based pharmacokinetic (PBPK) modeling. The effect of rifampin (a strong inducer of CYP3A4 and moderate inducer of CYP1A2), administered at a 600 mg dose once daily, on maribavir pharmacokinetics was assessed in a clinical phase 1 DDI study in healthy participants. A full PBPK model for maribavir was developed and verified using in vitro and clinical pharmacokinetic data from phase 1 studies. The verified PBPK model was then used to simulate maribavir DDI interactions with various CYP3A4 inducers and inhibitors. The DDI study results showed that coadministration with rifampin decreased the maribavir maximum plasma concentration (Cmax), area under the plasma concentration‐time curve (AUC), and trough concentration (Ctrough) by 39%, 60%, and 82%, respectively. Based on the results from the clinical DDI study, the coadministration of maribavir with rifampin is not recommended. The PBPK model did not predict a clinically significant effect of CYP3A4 inhibitors on maribavir exposure; however, it predicted that strong or moderate CYP3A4 inducers, including carbamazepine, efavirenz, phenobarbital, and phenytoin, may reduce maribavir exposure to a clinically significant extent, and may prompt the consideration of a maribavir dosing increase, in accordance with local approved labels and/or regulations.
Dolutegravir is an integrase strand transfer inhibitor (INSTI) licensed for use in HIV-1 infection and is an inhibitor of organic cation transporter 2 (OCT2). This study assessed the effect of ...dolutegravir on the pharmacokinetics of metformin, an OCT2 substrate.
This was an open-label, parallel-group, 3-period crossover study in healthy adult subjects. Subjects were enrolled into 1 of 2 treatment cohorts (15 subjects/cohort) receiving metformin 500 mg q12h for 5 days in period 1; metformin 500 mg q12h plus dolutegravir 50 mg q24h (cohort 1) or 50 mg q12h (cohort 2) for 7 days in period 2; and metformin 500 mg q12h for 10 days in period 3. There were no washout periods between treatments. Effects of dolutegravir on metformin transport and paracellular permeability were evaluated in vitro.
Co-administration of dolutegravir 50 mg q24h increased metformin area under the curve(0-τ) by 79% and Cmax by 66%, whereas dolutegravir 50 mg q12h increased metformin area under the curve(0-τ) and Cmax by 145% and 111%, respectively. Metformin t(1/2) remained unchanged. Increased metformin exposure during dolutegravir co-administration returned to period 1 levels after dolutegravir discontinuation in period 3. Co-administration of dolutegravir and metformin was well tolerated. In vitro, dolutegravir was not a clinically relevant inhibitor of OCT1, OCT3, multidrug and toxin extrusion protein 1, multidrug and toxin extrusion protein 2-K, or plasma membrane monoamine transporter, and it did not affect metformin paracellular permeability or uptake into an intestinal cell line.
Dolutegravir significantly increased metformin plasma exposure, which can be partially explained by OCT2 inhibition. It is recommended that dose adjustments of metformin be considered to maintain optimal glycemic control when patients are starting/stopping dolutegravir while taking metformin.
Maribavir is an oral benzimidazole riboside for treatment of post‐transplant cytomegalovirus (CMV) infection/disease that is refractory to prior antiviral treatment (with or without resistance). ...Through competitive inhibition of adenosine triphosphate, maribavir prevents the phosphorylation actions of UL97 to inhibit CMV DNA replication, encapsidation, and nuclear egress. Maribavir is active against CMV strains with viral DNA polymerase mutations that confer resistance to other CMV antivirals. After oral administration, maribavir is rapidly and highly absorbed (fraction absorbed >90%). The approved dose of 400 mg twice daily (b.i.d.) achieves a steady‐state area under the curve per dosing interval of 128 h*μg/mL and trough concentration of 4.90 μg/mL (13.0 μM). Maribavir is highly bound to human plasma proteins (98%) with a small apparent volume of distribution of 27.3 L. Maribavir is primarily cleared by hepatic CYP3A4 metabolism; its major metabolite, VP44669 (pharmacologically inactive), is excreted in the urine and feces. There is no clinically relevant impact on maribavir pharmacokinetics by age, sex, race/ethnicity, body weight, transplant type, or hepatic/renal impairment status. In phase II dose‐ranging studies, maribavir showed similar rates of CMV viral clearance across 400, 800, or 1200 mg b.i.d. groups, ranging from 62.5–70% in study 202 (NCT01611974) and 74–83% in study 203 (EudraCT 2010–024247‐32). In the phase III SOLSTICE trial (NCT02931539), maribavir 400 mg b.i.d. demonstrated superior CMV viremia clearance at week 8 versus investigator‐assigned treatments, with lower treatment discontinuation rates. Dysgeusia, nausea, vomiting, and diarrhea were commonly experienced adverse events among patients treated with maribavir in clinical trials.
Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug‐drug interactions, we examined the effects of multiple doses ...of maribavir on cytochrome P450 (CYP) 2D6 and P‐glycoprotein (P‐gp) activity using probe substrates in healthy volunteers. During this phase 1 open‐label study (NCT02775240), participants received the probe substrates digoxin (0.5 mg) and dextromethorphan (30 mg) before and after maribavir (400 mg twice daily for 8 days). Serial plasma samples were analyzed for digoxin, dextromethorpha, dextrorphan, and maribavir concentrations. Pharmacokinetic parameters were calculated (noncompartmental analysis) and analyzed with a linear mixed‐effects model for treatment comparison to estimate geometric mean ratios (GMRs) and 90% confidence intervals (CIs). CYP2D6 polymorphisms were genotyped using polymerase chain reaction. Overall, 17 of 18 participants (94.4%) completed the study. All participants were genotyped as CYP2D6 intermediate/extensive metabolizers. GMR (90%CI) of digoxin Cmax, AUClast, and AUC0‐∞ with and without maribavir was 1.257 (1.139‐1.387), 1.187 (1.088‐1.296), and 1.217 (1.110‐1.335), respectively, outside the “no‐effect” window (0.8‐1.25). GMR (90%CI) of dextromethorphan AUClast and AUClast ratio of dextromethorphan/dextrorphan were 0.877 (0.692‐1.112) and 0.901 (0.717‐1.133), respectively, marginally outside the no‐effect window, although large variability was observed in these pharmacokinetic parameters. Pharmacokinetic parameters of dextrorphan were unaffected. Maribavir inhibited P‐gp activity but did not affect CYP2D6 activity. Maribavir's effect on the pharmacokinetics of P‐gp substrates should be evaluated individually, and caution should be exercised with P‐gp substrates with narrow therapeutic windows.
Background. Dolutegravir (DTG), a once-daily, human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF). ...Methods. ING116070 is an ongoing, single-arm, open-label, multicenter study in antiretroviral therapy–naive, HIV-1–infected adults. Subjects received DTG (50 mg) plus abacavir/lamivudine (600/300 mg) once daily. The CSF and plasma (total and unbound) DTG concentrations were measured at weeks 2 and 16. The HIV-1 RNA levels were measured in CSF at baseline and weeks 2 and 16 and in plasma at baseline and weeks 2, 4, 8, 12, and 16. Results. Thirteen white men enrolled in the study; 2 withdrew prematurely, 1 because of a non–drug-related serious adverse event (pharyngitis) and 1 because of lack of treatment efficacy. The median DTG concentrations in CSF were 18 ng/mL (range, 4–23 ng/mL) at week 2 and 13 ng/mL (4–18 ng/mL) at week 16. Ratios of DTG CSF to total plasma concentration were similar to the unbound fraction of DTG in plasma. Median changes from baseline in CSF (n = 11) and plasma (n = 12) HIV-1 RNA were -3.42 and -3.04 log10 copies/mL, respectively. Nine of 11 subjects (82%) had plasma and CSF HIV-1 RNA levels <50 copies/mL and 10 of 11 (91%) had CSF HIV-1 RNA levels <2 copies/mL at week 16. Conclusions. The DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting that DTG achieves therapeutic concentrations in the central nervous system. The HIV-1 RNA reductions were similar in CSF and plasma. Clinical Trials Registration. NCT01499199.
Aim
Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This ...analysis aimed to characterize the population pharmacokinetics of dolutegravir in treatment‐naive patients and to evaluate the influence of patient covariates.
Methods
A population pharmacokinetic model was developed using a non‐linear mixed effect modelling approach based on data from 563 HIV‐infected, treatment‐naive adult patients in three phase 2/3 trials who received dolutegravir (ranging from 10–50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine.
Results
The pharmacokinetics of dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h–1, 17.4 l, 2.24 h−1, and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady‐state dolutegravir plasma exposure was relatively small (<32%) and was not considered clinically significant. Race/ethnicity, HBV/HCV co‐infection, CDC classification, albumin, creatinine clearance, alanine aminotransferase or aspartate aminotransferase did not influence the pharmacokinetics of dolutegravir in this analysis.
Conclusions
A population model that adequately characterizes dolutegravir pharmacokinetics has been developed. No dolutegravir dose adjustment by patient covariates is necessary in HIV‐infected treatment‐naive patients.
Aim
Dolutegravir (DTG; S/GSK1349572) is under clinical development as a once daily, unboosted integrase inhibitor for the treatment of HIV infection. The effect of DTG on glomerular filtration rate ...(GFR), effective renal plasma flow (ERPF), and creatinine clearance (CLcr) was evaluated in 34 healthy volunteers.
Methods
Subjects received DTG 50 mg (once daily or twice daily) or placebo for 14 days. GFR was measured by iohexol plasma clearance, ERPF was assessed by para‐aminohippurate plasma clearance and CLcr was measured by 24 h urine collection.
Results
All treatments were generally well tolerated. A modest decrease (10–14%) in CLcr was observed, consistent with clinical study observations. DTG 50 mg once daily and twice daily had no significant effect on GFR or ERPF compared with placebo over 14 days in healthy subjects.
Conclusions
These findings support in vitro data that DTG increases serum creatinine by the benign inhibition of the organic cation transporter 2, which is responsible for tubular secretion of creatinine.
Maribavir was approved by the US Food and Drug Administration for the treatment of patients aged ≥12 years and weighing ≥35 kg with posttransplant cytomegalovirus infection/disease refractory ...(with/without resistance) to valganciclovir, ganciclovir, cidofovir, or foscarnet, with an oral dose of 400 mg twice daily. With no pediatric clinical data available and difficulty in trial recruitment, population pharmacokinetic modeling and simulations were conducted to predict the pharmacokinetics and inform maribavir dosing in adolescents.
The effect of food composition, tablet crushing, and antacid coadministration on maribavir pharmacokinetics was assessed in 2 Phase 1 studies in healthy adults. In the first, a single maribavir ...400‐mg dose was administered under fasting conditions, with a low‐fat/low‐calorie or a high‐fat/high‐calorie meal. In the second, a single maribavir 100‐mg dose was administered under fasting conditions, as a crushed tablet, or as a whole tablet alone or with an antacid. The 90% confidence intervals of the geometric mean ratios were within 80%‐125% for area under the concentration‐time curve (AUC), but not for maximum plasma concentration (Cmax) for low‐fat/low‐calorie and high‐fat/high‐calorie meals versus fasting or for whole tablet with antacid versus whole tablet alone. The 90% confidence intervals of the geometric mean ratios for AUC and Cmax were within 80%‐125% for crushed versus whole tablet. Maribavir median time to Cmax value in plasma under fed conditions was delayed versus fasting conditions, but there was no statistical difference for crushed versus whole tablet or with versus without antacid. As the antiviral efficacy of maribavir is driven by AUC but not Cmax, findings suggest that maribavir can be administered with food or antacids or as a crushed tablet.
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