Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report.

This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.

Effect of Food, Crushing of Tablets, and Antacid Coadministration on Maribavir Pharmacokinetics in Healthy Adult Participants: Results From 2 Phase 1, Open-Label, Randomized, Crossover Studies.

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.

Breaking the Silence: An Epidemiological Report on Asian American and Pacific Islander Youth Mental Health and Suicide (1999-2021).

BACKGROUND: Limited studies have focused on recent trends in Asian American and Pacific Islander (AAPI) youth suicide. This study aimed to evaluate epidemiological trends in AAPI youth suicide and reports of depressive symptoms among Asian and Pacific Islander youth in the USA. METHODS: This cross-sectional study analyzed mortality data from the Centers for Disease Control Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) and reports of depressive symptoms from the Youth Risk Behaviour Surveillance System (YRBSS). Data from 1999 to 2021 were analyzed for suicide rates and methods used among AAPI youth aged 5-24 years. YRBSS data from 1991 to 2021 were analyzed for depressive symptoms reported by Asian American (AA) 9th-12th graders. RESULTS: From 1999 to 2021, 4747 AAPI youth died by suicide in the USA. Rates of suicide doubled from 3.6 to 7.1 per 100,000 during 1999-2021, with an increasing trend observed from 2014 onwards. The most common methods of suicide deaths in this population were suffocation, firearms and poisoning. Rates of suicide were higher among AA males than females, although more AA females reported depressive symptoms, including suicidal planning and attempts. CONCLUSION: This study shows a concerning increase in suicide rates among AAPI youth over 1999-2021. Suffocation, firearms and poisoning were the most common methods used. While more AAPI males died by suicide, AA females reported higher rates of depressive symptoms. These findings highlight the urgent need for targeted prevention strategies and clinical interventions for this vulnerable population. The study also emphasizes the importance of addressing mental health stigma to improve reporting and support for Asian American, Native Hawaiian and Pacific Islander (AANHPI) youth.

Maribavir: Mechanism of action, clinical, and translational science.

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.

Physiologically Based Pharmacokinetic Modeling for Maribavir to Inform Dosing in Drug-Drug Interaction Scenarios with CYP3A4 Inducers and Inhibitors.

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.

A Phase I Randomized Trial of Once-Daily Versus Twice-Daily Recombinant Human Parathyroid Hormone (1-84) for Hypoparathyroidism.

Recombinant human parathyroid hormone (1-84), rhPTH(1-84), is an approved adjunctive treatment to oral calcium and active vitamin D for adult patients with hypoparathyroidism; however, there is limited information on the effect of twice daily (BID) dosing of rhPTH(1-84). This was a phase I, open-label, randomized, crossover, multicenter study conducted in adult patients with chronic hypoparathyroidism. The primary objective was to assess the pharmacokinetic profile and pharmacodynamic effects of 1 day of treatment with rhPTH(1-84) administered subcutaneously at 25 µg BID, 50 µg BID, and 100 µg once daily (QD) with or without supplemental oral calcium. Safety and tolerability were evaluated as secondary objectives. In total, 33 patients with chronic hypoparathyroidism completed the study. Treatment with rhPTH(1-84), both BID and QD, over the short-term maintained serum calcium, lowered serum phosphorus, decreased urinary calcium excretion, and increased urinary phosphorus excretion. The decrease in urinary calcium excretion was numerically greater for BID than QD. Generally, baseline-adjusted pharmacokinetic parameters including area under the curve and maximum observed concentration increased with increasing rhPTH(1-84) dose, although this effect was not dose proportional. No new safety findings were observed. Our study revealed no differences thought to be clinically meaningful in pharmacokinetic or pharmacodynamic parameters with BID versus QD rhPTH(1-84) dosing. Future long-term studies are warranted to further elucidate the effects of alternative dosing strategies. © 2023 Takeda Development Center Americas, Inc and The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Pharmacokinetics and Safety Evaluation of Maribavir in Healthy Japanese and Matched White Participants: A Phase 1, Open-Label Study.

This phase I study compared pharmacokinetics and safety of maribavir in Japanese and White participants, and evaluated dose proportionality in Japanese participants. Under fasting conditions, 12 healthy adult participants of Japanese descent and 12 matched White participants received a single 400-mg dose of maribavir. Japanese participants received 2 further doses of maribavir: 200 mg and 800 mg, or 800 mg and 200 mg, separated by a ≥72-hour washout period. Serial blood samples were collected up to 24 hours after dosing for pharmacokinetic assessments. Following the 400-mg dose, the geometric mean ratios (90% confidence interval) of Japanese versus White participants were 110% (91.7%-133%) for maximum plasma concentration, 122% (96.8%-155%) for area under the plasma concentration-time curve (AUC) from time of dosing to the last measurable concentration, and 125% (98.0%-160%) for AUC extrapolated to infinity. In Japanese participants, maribavir AUC extrapolated to infinity and AUC from time of dosing to the last measurable concentration increased in a dose-proportional fashion over 200-800 mg; maximum plasma concentration increased less than dose proportionally. Seven participants reported treatment-emergent adverse events (TEAEs; Japanese participants, 400 mg: 2 [16.7%], 200 mg: 1 [8.3%]; White participants, 400 mg: 4 [33.3%]), all mild and most commonly dysgeusia. No serious TEAEs or TEAEs leading to discontinuation were reported. This study demonstrated higher maribavir systemic exposure in Japanese than White participants and similar safety outcomes. This difference in exposure is not considered clinically important and its significance remains to be determined.

Population pharmacokinetic modeling and simulation of maribavir to support dose selection and regulatory approval in adolescents with posttransplant refractory cytomegalovirus.

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.

Maribavir Pharmacokinetics and Safety in Participants With Moderate Hepatic Impairment: A Phase 1, Open-Label, Single-Dose, Parallel Group Study.

Maribavir, an orally bioavailable antiviral, has shown superior activity against posttransplant cytomegalovirus infection compared with conventional antivirals. It is primarily metabolized in the liver. This open-label, single-center study evaluated the effect of hepatic impairment on the pharmacokinetics of maribavir in nontransplant participants. A single 200-mg dose of maribavir was administered orally under fasting conditions to participants with moderate hepatic impairment (Child-Pugh class B) (n = 10) and healthy controls (n = 10) matched for age, weight, sex, and smoking status. Compared with participants with normal hepatic function, maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time 0 to infinity values for maribavir in participants with moderate hepatic impairment were 1.346-fold (90%CI of geometric mean ratio, 1.091-1.660) and 1.261-fold (0.889-1.787) higher, respectively. However, Cmax and AUC values for unbound maribavir were comparable. For VP 44469, the main metabolite of maribavir, the Cmax and AUC from time 0 to infinity values were 1.190-fold (0.836-1.693) and 1.309-fold (1.007-1.702) higher, respectively, in participants with moderate hepatic impairment. In total, 7 mild treatment-emergent adverse events were reported, all in the moderate hepatic impairment group. Dysgeusia was the most frequently reported treatment-emergent adverse event, at a frequency of 50%. These results indicated that total maribavir concentrations were mildly increased in participants with moderate hepatic impairment, while unbound concentrations were unaffected. Similar maribavir pharmacokinetics in participants with moderate hepatic impairment and normal hepatic function suggest that dose adjustment may not be required for patients with moderate hepatic impairment.

Pharmacokinetics of Budesonide Oral Suspension in Children and Adolescents With Eosinophilic Esophagitis.

The pharmacokinetic (PK) profile of budesonide oral suspension (BOS) was evaluated during a phase 2, randomized, double-blind, placebo-controlled, dose-ranging study in pediatric patients with eosinophilic esophagitis (EoE) (MPI 101-01/NCT00762073). Non-compartmental methods were used to calculate PK parameters in 37 patients after receiving morning doses of BOS, with volume and dose adjusted for age (low dose: 0.35 or 0.5 mg; high dose: 1.4 or 2.0 mg [2-9 or 10-18 years old, respectively]). Relationships between apparent oral clearance and volume of distribution, and bodyweight and body mass index were also evaluated. Budesonide systemic exposure increased with BOS dose. After oral administration, time to maximum plasma budesonide concentration occurred ~1 hour post dose and the half-life of budesonide was 3.3-3.5 hours. PK parameters were similar between age groups for low- and high-dose BOS, indicating that volume and dose adjustments for age were appropriate for pediatric patients with EoE. BOS was well tolerated.

A Pharmacokinetic Bridging Study to Compare Systemic Exposure to Budesonide between Budesonide Oral Suspension and ENTOCORT EC in Healthy Individuals.

BACKGROUND AND OBJECTIVES: Currently, there are no US FDA-approved therapies for eosinophilic esophagitis (EoE). Budesonide oral suspension (BOS; SHP621, TAK-721) is a viscous, muco-adherent, oral formulation of budesonide that is in phase III development for the treatment of EoE. BOS 2 mg twice daily was studied in 12- and 36-week phase III studies for the induction and maintenance of clinical remission in adults and adolescents with EoE (NCT02605837 and NCT02736409). ENTOCORT EC is a gelatin capsule formulation of budesonide that is FDA-approved for the treatment of mild-to-moderate active Crohn's disease (CD) in adults and children. This study compared the systemic exposure to budesonide from BOS with that from ENTOCORT EC, aiming to provide the pharmacokinetic (PK) bridge to the safety data of ENTOCORT EC. METHODS: Healthy adult volunteers (n = 22) were enrolled in an open-label, single-center, crossover study. Participants received a single oral dose of BOS 2 mg and a single oral dose of ENTOCORT EC 9 mg under fasting conditions in a randomized sequence, with a 48-h washout period between treatments. PK parameters were calculated by non-compartmental analysis and compared between treatments using a mixed-effects model with sequence and treatment as fixed effects and individuals within sequence as a random effect. RESULTS: Plasma budesonide concentrations showed that budesonide was absorbed significantly faster from BOS 2 mg than from ENTOCORT EC 9 mg, with peak concentrations reached at 1.5 and 4 h, respectively (p < 0.001). Systemic exposure to budesonide after a single oral dose of BOS 2 mg was lower than that observed after a single oral dose of ENTOCORT EC 9 mg; the least squares geometric mean maximum plasma concentration and the area under the concentration-time curve from the time of dosing to infinity and from the time of dosing to the last measurable concentration of budesonide after BOS 2 mg were 71.1%, 33.5%, and 33.6% of those after ENTOCORT EC 9 mg, respectively. No notable differences in treatment-emergent adverse events were observed between individuals treated with either drug; all events were mild and none resulted in discontinuation from the study. CONCLUSIONS: This study demonstrated that systemic exposure to budesonide after a single oral dose of BOS 2 mg was lower than that after a single oral dose of ENTOCORT EC 9 mg. These results provide PK bridging data to compare BOS with therapeutic doses of ENTOCORT EC with respect to safety information.

Evaluation of the Effect of Maribavir on Cardiac Repolarization in Healthy Participants: Thorough QT/QTc Study.

Maribavir is an orally bioavailable benzimidazole riboside in clinical development for treatment of cytomegalovirus infection in patients who undergo transplantation. Maribavir was evaluated in a thorough QT (TQT) study to determine any effects on cardiac repolarization. The effect of maribavir 100 and 1,200 mg oral doses on the baseline-adjusted and placebo-adjusted corrected QT (QTc) interval (delta delta QTc (ddQTc)) and other electrocardiogram (ECG) parameters was assessed in a randomized, phase I, placebo-controlled, four-period crossover study in healthy participants (men and women ages 18-50 years). Additionally, maribavir pharmacokinetics, safety, and tolerability were investigated. Moxifloxacin (400 mg) was used as a positive control to demonstrate the study's ability to detect QT prolongation. Digital 12-lead Holter ECG monitoring was performed over 22 hours following study drug administration. Individual, Fridericia's, and Bazett's QTc intervals were calculated. Of 52 randomized participants (29 ± 8.1 years old; 31 men (60%)), 50 (96%) completed the study. For both 100-mg and 1200-mg doses of maribavir, analysis of ddQTc demonstrated that the upper bound of the two-sided 90% confidence interval was below the 10-ms threshold at all time points. The concentration-effect analysis demonstrated no relationship between ddQTc and plasma concentrations of maribavir (and its metabolite). There were no clinically meaningful changes in heart rate and systolic blood pressure. The most common adverse event was dysgeusia; no serious adverse events were reported. This TQT study demonstrated that maribavir did not have impact on cardiac repolarization.

Effects of Maribavir on P-Glycoprotein and CYP2D6 in Healthy Volunteers.

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.

Outcomes After Minimally Invasive Parafascicular Surgery for Intracerebral Hemorrhage: A Single-Center Experience.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) comprises 10%-15% of strokes with a high mortality (40%) and low rates of functional independence within 6 months (25%). Minimally invasive parafascicular surgery has emerged as a potentially safer option for ICH management. METHODS: Data from 25 patients who underwent channel-based ICH evacuation were retrospectively collected regarding demographics, clinical presentation, neuroimaging characteristics, follow-up modified Rankin Scale (mRS) score, Glasgow Coma Scale (GCS) score, and disposition. RESULTS: Sixteen patients were male (64%) and 9 were female (36%), with a mean age of 52 years. There were 4 frontal, 1 occipital, and 20 basal ganglia hemorrhages; 15 (60%) showed intraventricular extension. Seventeen ICHs (68%) and 6 of 7 patient deaths (86%) were left sided. The mean volume was 46 cm3 (range, 13.1-101.2 cm3), and the mean clot reduction was 92%. Left-sided ICH (P = 0.014) and the presence of intraventricular hemorrhage (P = 0.038) were associated with worsened postoperative GCS score. Larger hemorrhages were associated with mortality (66 cm3 vs. 38 cm3; P < 0.005). With a mean follow-up time of 5 months, the median follow-up mRS score was 3.5 (vs. 4 preoperatively), and median follow-up GCS was 15 (vs. 10 preoperatively). Patients with higher postoperative mRS scores and lower postoperative GCS were more likely to die. CONCLUSIONS: BrainPath-mediated transsulcal approaches are associated with improved mRS and GCS scores, with low rates of residual hematoma, although further data are needed via controlled studies to determine the importance of hemorrhage location and size, timing of surgical intervention, and long-term patient outcomes.

A Two-Way Steady-State Pharmacokinetic Interaction Study of Doravirine (MK-1439) and Dolutegravir.

INTRODUCTION: Doravirine, a non-nucleoside reverse-transcriptase inhibitor in development for the treatment of patients with human immunodeficiency virus-1 infection, has potential to be used concomitantly in antiretroviral therapy with dolutegravir, an integrase strand transfer inhibitor. The pharmacokinetic interactions between these drugs were therefore assessed. METHODS: Oral formulations of doravirine and dolutegravir were dosed both individually and concomitantly once daily in healthy adults. Twelve subjects (six were male), 23-42 years of age, were enrolled and 11 completed this phase I, open-label, three-period, fixed-sequence study per protocol; one subject was discontinued for a positive cotinine test at admission to period 2. In period 1, dolutegravir 50 mg was administered for 7 days. After a 7-day washout, doravirine 200 mg was dosed for 7 days in period 2, followed (without washout) by both doravirine and dolutegravir simultaneously for 7 days in period 3. Plasma samples were taken to determine dolutegravir and doravirine concentrations. RESULTS: The steady-state concentration 24 h post-dose (C24) of dolutegravir was not substantially altered by co-administration of doravirine multiple doses; area under the plasma concentration-time curve from dosing to 24 h post-dose (AUC0-24), maximum concentration (C max), and C24 geometric mean ratios were 1.36, 1.43, and 1.27, respectively. The pharmacokinetics of doravirine was not affected by multiple doses of dolutegravir (geometric mean ratios: 1.00, 0.98, and 1.06 for AUC0-24, C24, and C max, respectively). Both drugs were generally well tolerated. CONCLUSION: The results of this study demonstrate that concomitant administration of doravirine and dolutegravir in healthy subjects causes no clinically significant alteration in the pharmacokinetic and safety profiles of the two drugs, thereby supporting further evaluation of co-administration of these agents for human immunodeficiency virus-1 treatment.

No clinically significant pharmacokinetic interactions between dolutegravir and daclatasvir in healthy adult subjects.

BACKGROUND: Daclatasvir (DCV) is an NS5A replication complex inhibitor recently approved for chronic hepatitis C virus treatment. METHODS: To assess drug interactions between the HIV integrase strand transfer inhibitor dolutegravir (DTG) and DCV, subjects were randomized into 1 of 2 sequences in an open-label, 3-period, crossover study. Subjects received either DTG 50 mg once daily or DCV 60 mg once daily for 5 days in periods 1 and 2 and DTG 50 mg plus DCV 60 mg once daily for 5 days in period 3, with no washout between periods 2 and 3. Between periods 1 and 2, there was a washout period of at least 7 days. RESULTS: The geometric least-squares mean ratios (90 % confidence intervals) of DCV area under the concentration-time curve over a dosing interval (AUC0-τ), maximum observed concentration (Cmax), and concentration at the end of the dosing interval (Cτ) were 0.978 (0.831-1.15), 1.03 (0.843-1.25), and 1.06 (0.876-1.29), respectively, when DCV was administered with DTG compared with DCV alone. Compared with DTG alone, coadministration of DTG with DCV increased DTG AUC0-τ, Cmax, and Cτ by approximately 33, 29, and 45 %, respectively. CONCLUSIONS: DCV plasma exposure was not meaningfully affected by DTG. Coadministration of DTG with DCV resulted in slight increases in DTG AUC0-τ, Cmax, and Cτ. Accumulated safety and tolerability data in humans receiving DTG to date suggests this effect is not considered clinically significant. DTG and DCV can be coadministered without dose adjustment. TRIAL REGISTRATION: Registered on March 6, 2014 with ClinicalTrials.gov; registration number: NCT02082808 and as Study ID: 201102 on the ViiV Clinical Study Registry.

The Effect of Dolutegravir on the Pharmacokinetics of Metformin in Healthy Subjects.

BACKGROUND: 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. DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Effect of carbamazepine on dolutegravir pharmacokinetics and dosing recommendation.

PURPOSE: Dolutegravir (DTG) is primarily metabolized by UGT1A1 with CYP3A as a minor route. Carbamazepine (CBZ) is a potent inducer of these enzymes; thus, the effect of oral extended-release CBZ on DTG pharmacokinetics (PK) was evaluated to provide dose recommendation when co-administered. METHODS: This was a single-center, open-label, fixed-sequence, crossover study in healthy adults. Subjects received three treatments: DTG 50 mg every 24 h (q24h) × 5 days in period 1, followed by CBZ 100 mg every 12 h (q12h) × 3 days, then 200 mg q12h × 3 days, then 300 mg q12h × 10 days in period 2, and DTG 50 mg q24h + CBZ 300 mg q12h × 5 days in period 3. No washout intervals occurred. Each dose was administered with a moderate-fat meal. Serial PK samples for DTG were collected on day 5 of periods 1 and 3. Plasma DTG PK parameters were determined with non-compartmental analysis. Geometric least-squares mean ratios (GMRs) and 90 % confidence intervals (CIs) were generated by the mixed-effect model for within-subject treatment comparisons. Safety assessments were performed throughout the study. RESULTS: Sixteen subjects enrolled; 14 completed the study. CBZ significantly reduced DTG exposure: GMRs (90 % CI) for DTG + CBZ versus DTG alone were 0.51 (0.48-0.549), 0.67 (0.61-0.73), and 0.27 (0.24-0.31) for area under the curve from time zero to the end of the dosing interval (AUC(0-τ)), maximum observed plasma concentration (Cmax), and plasma concentration at the end of the dosing interval (Cτ), respectively. DTG alone and co-administered with CBZ was well tolerated. CONCLUSION: Integrase strand transfer inhibitor-naive subjects taking CBZ should receive DTG 50 mg twice daily versus once daily, as is recommended with other potent UGT1A/CYP3A inducers. ClinicalTrials.gov: NCT01967771.