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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 (C

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 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.

The Inaugural 2018 Medical Student Neurosurgery Training Camp successfully launched a collaborative effort to better prepare medical students pursuing careers in neurological surgery. In 2019, the Medical Student Neurosurgery Training Camp expanded to two campus to better facilitate student participation. Additionally, the new, pilot curriculum emphasized more hands-on experience, which was generally well received. Overall, student participation and preparation improved in 2019. The Medical Student Training Camp aims to continue expansion in 2020 and develop tools that relieve the administrative burdens place on student planning committees.

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.

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

Introduction Maribavir, a potent and orally bioavailable antiviral, is being evaluated in Phase 3 trials for the treatment of cytomegalovirus (CMV) infections in transplant patients. Often numerous concomitant medications are administered to these patients to manage their comorbidities. A thorough evaluation of maribavir potential for drug–drug interactions (DDIs) is warranted and required for the regulatory approval. Objectives To thoroughly evaluate potential DDIs for maribavir. Methods Extensive in vitro studies were conducted to evaluate the potential involvement of cytochrome P450s (CYPs), uridine diphosphate glucuronosyltransferases (UGTs) and transporters on the disposition of maribavir, as well as the inhibitory and induction effect of maribavir on these enzymes and transporters. Clinical Phase 1 studies included a human mass-balance study, two probe-cocktail studies, and five DDI studies with ketoconazole, rifampin, antacid, voriconazole, and tacrolimus. Results Maribavir is metabolized primarily in the liver through CYP3A4 (70–85%) and CYP1A2 (15–30%). Renal clearance is a minor route ( Conclusions Maribavir has low risk for DDI. Inhibitors of CYP3A4 and/or P-gp may increase maribavir exposure, but dose adjustment of maribavir is not necessary. Potent inducers of CYP3A4 and P-gp decrease maribavir exposure, necessitating maribavir dose increase. Maribavir may increase exposure of immunosuppressants, such as tacrolimus. Therefore, monitoring of concomitant immunosuppressants' blood concentration should be considered at initiation, co-administration, and discontinuation of maribavir. Maribavir is not expected to interact with other concurrent medications.

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 (

Background: Dolutegravir (DTG; Tivicay; ViiV Healthcare, Research Triangle Park, NC) is an HIV-1-unboosted integrase inhibitor with no cytochrome P450 or uridine 5′diphosphate-glucuronosyltransferase inhibition or induction. As DTG is administered to HIV-1–infected women receiving oral contraceptives, assessing the potential for drug interactions was warranted. Objective: To determine the impact of DTG on the pharmacokinetics (PK) and pharmacodynamics (PD) of a common oral contraceptive, norgestimate/ethinyl estradiol (NGM/EE; Ortho-Cyclen; Ortho-McNeil-Janssen Pharmaceuticals, Inc, Raritan, NJ). Methods: This randomized, 2-period, double-blind, placebo-controlled study was conducted within 1 menstrual cycle at 1 clinical center in the United States; 16 women were enrolled. Participants received NGM 0.25 mg/EE 0.035 mg throughout the study. During days 1 to 10, they were randomized to receive twice-daily DTG 50 mg or matching placebo with food and switched to the other treatment during days 12 to 21. Results: Ratios of area under the concentration-time curve from time 0 until end of the dosage interval (AUC0-τ), maximum plasma concentration, and concentration at the end of the dosage interval of norelgestromin with DTG treatment to the same PK parameters with placebo treatment were 0.975, 0.890, and 0.932, respectively; for EE, ratios were 1.03, 0.99, and 1.02, respectively. No significant differences in luteinizing hormone, follicle-stimulating hormone, and progesterone were detected on days 1, 10, 11, 21, and 22. DTG steady-state AUC0-τ was similar to historical data. No severe or grade 3/4 adverse events occurred. Conclusions: DTG had no effect on NGM/EE PK or PD. NGM/EE can be administered with DTG without dose adjustment.

All commercially available integrase inhibitors are 2-metal binders and may be affected by co-administration with metal cations. The purpose of this study was to evaluate the effect of calcium and iron supplements on dolutegravir pharmacokinetics and strategies (dose separation and food) to attenuate the effects if significant reductions in dolutegravir exposure were observed. This was an open-label, crossover study that randomized 24 healthy subjects into 1 of 2 cohorts to receive 4 treatments: (1) dolutegravir alone, fasting; (2) dolutegravir with calcium carbonate or ferrous fumarate, fasting; (3) dolutegravir with calcium carbonate or ferrous fumarate with a moderate-fat meal; (4) dolutegravir administered 2 hours before calcium carbonate or ferrous fumarate, fasting. Plasma dolutegravir AUC(0-∞), Cmax , and C24 were reduced by 39%, 37%, and 39%, respectively, when co-administered with calcium carbonate while fasting and were reduced by 54%, 57%, and 56%, respectively, when co-administered with ferrous fumarate while fasting. Dolutegravir administration 2 hours before calcium or iron supplement administration (fasted), as well as administration with a meal, counteracted the effect. Dolutegravir and calcium or iron supplements can be co-administered if taken with a meal. Under fasted conditions, dolutegravir should be administered 2 hours before or 6 hours after calcium or iron supplements.

Introduction Maribavir is a potent and orally bioavailable antiviral with a novel mechanism of action against cytomegalovirus (CMV). The efficacy and safety of maribavir for treatment of CMV infections are being evaluated in ongoing Phase 3 trials. Characterization of drug–drug interaction (DDI) properties of maribavir is necessary in informing potential DDIs with co-medications. Objective To evaluate the potential cytochrome p450 and p-glycoprotein–mediated drug–drug interaction by maribavir. Methods Cytochrome P450 (CYP) reversible inhibition: Probe substrates of CYPs were incubated with human liver microsomes (HLM) and maribavir. Percent remaining CYP activity was plotted against maribavir concentrations for IC50 determination. Time-dependent inhibition (TDI) for CYPs: After pre-incubation with maribavir for varying durations, percent remaining CYP activity in HLM was measured. The concentration at half-maximal inactivation (KI) and maximum inactivation rate constant (kinact) were calculated. CYP induction: After treating human hepatocytes with maribavir for three days, CYP mRNA expression was plotted against maribavir concentrations to determine half-maximal induction concentration (EC50) and maximal fold induction (Emax). P-glycroprotein (P-gp) inhibition: Bi-directional transport of digoxin in Caco-2 cells with maribavir was measured and IC50 calculated by plotting percent transporter activity against maribavir concentration. Results Maribavir is not a reversible inhibitor of CYP2A6, CYP2B6, CYP2C8, CYP2D6, CYP2E1, or CYP3A4 and is a weak inhibitor of CYP1A2, CYP2C9, and CYP2C19 (IC50 40, 18, and 35 µM). Maribavir is not a TDI of CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 but a weak TDI for CYP3A (KI 41.2 μM, kinact 0.0117 min−1). Maribavir is not an inducer of CYP1A2 or CYP2B6 mRNA but is a weak, possibly donor-dependent inducer of CYP3A4 mRNA. Maribavir is a weak inhibitor of P-gp (IC50 33.7 µM). Conclusions Maribavir is not expected to affect exposures of substrates of major CYPs or P-gp when co-administered at therapeutic dose of 400 mg BID, based on its estimated maximal unbound plasma concentration (Cmax,u) of 0.74 μM in transplant patients with CMV infection.

Introduction Maribavir, a potent and orally bioavailable antiviral, is being evaluated in Phase 3 trials for the treatment of CMV infections in transplant patients and received FDA Breakthrough Therapy designation. A thorough understanding of the clinical pharmacology of maribavir is necessary to guide the appropriate use of the drug in transplant patients who often have multiple comorbidities and require complex concurrent medication regimens. Objectives To summarize the clinical pharmacology data of maribavir. Methods Pharmacokinetic and pharmacodynamic assessments were performed in sixteen Phase 1 studies and three Phase 2 studies. Data were summarized to characterize maribavir's disposition (absorption, distribution, metabolism, and excretion) in healthy adult subjects and special populations (HIV-infected, hepatically impaired, renally impaired, and organ transplant recipients). A definitive QT study was conducted to evaluate the cardiac repolarization effect. The drug interaction risks were assessed using both nonclinical and clinical studies. Results Maribavir is primarily eliminated through the CYP3A4 pathway and has a half-life of 5–7 hours. Co-administration with food or antacid, or crushing the tablet, had no impact on maribavir's exposure. Maribavir binds to plasma proteins with unbound fraction estimated at 1.5% and can penetrate the blood–retinal barrier. No pharmacokinetic difference is found among healthy subjects, transplant patients, subjects with severe renal impairment, or moderate hepatic impairment. Maribavir's exposure is increased by 46% by ketoconazole and decreased by 61% by rifampin. Maribavir increases tacrolimus exposure by 51%, does not affect voriconazole exposure, and is not expected to affect exposures of most other concurrent medications. Maribavir has no effects on QT intervals. Conclusions Extensive clinical pharmacology data have been generated to support the clinical use and dose of maribavir for the treatment of CMV infections in transplant recipients. Maribavir can be taken with or without food. No maribavir dose adjustment is needed in patients with mild-to-moderate hepatic impairment or renal impairment or with concurrent medications, except for CYP3A4 inducers.

Prednisone, a corticosteroid frequently used to treat common AIDS-related illnesses and comorbidities, has been shown to induce drug metabolism. This study was performed to determine whether prednisone coadministration affected the pharmacokinetics of dolutegravir (DTG). In this open-label, repeat-dose study, 12 healthy subjects were administered DTG at 50 mg daily alone for 5 days and then with concomitant prednisone for 10 days (prednisone at 60 mg daily for 5 days, followed by a 5-day taper). Serial blood sampling and safety assessments were performed during the trial. Pharmacokinetic parameters were determined using noncompartmental methods and geometric least-square mean ratios, and 90% confidence intervals were generated. Coadministration of DTG and 5-day high-dose prednisone with a 5-day taper had a modest effect on DTG exposure. The area under the DTG plasma concentration-time curve, maximum observed DTG concentration, and 24-hour postdose DTG concentration were increased by 11%, 6%, and 17%, respectively, on day 10 of the combination. Similar results were observed after 5 days of DTG and prednisone. Dolutegravir and prednisone coadministration was well tolerated. The changes in plasma exposures of DTG in healthy individuals as a result of prednisone dosing were not clinically significant. No dose adjustment is required for DTG coadministered with prednisone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01425099.)

This study evaluated dolutegravir pharmacokinetics (PK) in subjects with moderate hepatic impairment compared to matched, healthy controls. In this open-label, parallel-group study, eight adult subjects with moderate hepatic impairment (Child-Pugh Score 7-9) and eight healthy subjects matched for gender, age, and body mass index received a single dolutegravir 50-mg dose. Following dosing, 72-hour PK sampling was performed to determine total and unbound dolutegravir concentrations. PK parameters were calculated using non-compartmental analysis. Geometric least squares mean ratios (GMR) and 90% confidence intervals (CIs) in subjects with hepatic impairment versus healthy subjects were generated by analysis of variance. Results showed that PK parameters of total plasma dolutegravir were similar between subject groups. The unbound fraction was higher in subjects with moderate hepatic impairment than in healthy subjects with GMR (90% CI) of 2.20 (1.62, 2.99) for unbound fraction at 3 hours post-dose and 1.76 (1.23, 2.51) for unbound fraction at 24 hours post-dose; this correlated with lower serum albumin concentrations and was not considered clinically significant. Dolutegravir was well tolerated in both groups; all adverse events were reported as minor. Although free fraction was increased, no dose adjustment is required for patients treated with dolutegravir who have mild to moderate hepatic impairment.

The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [ 14 C]dolutegravir at a dose of 20 mg (80 μCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives ( t 1/2 ) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.

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.

Background Cotreatment of tuberculosis (TB) and HIV among coinfected patients is now the standard of care. Rifampin (RIF) is a standard part of TB treatment but is a potent inducer of drug metabolizing enzymes. This study evaluated the effect of RIF or rifabutin (RBT) on the pharmacokinetics of the investigational HIV integrase inhibitor, dolutegravir (DTG). Methods Phase I pharmacokinetic drug interaction study. In arm 1, healthy subjects received 50 mg of DTG once daily for 7 days (period 1), then 50 mg of DTG twice daily for 7 days (period 2), then 50 mg of DTG twice daily together with 600 mg of RIF once daily for 14 days (period 3). In arm 2, subjects received 50 mg of DTG once daily for 7 days (period 1) then 50 mg of DTG once daily together with 300 mg of RBT once daily for 14 days (period 2). PK sampling was performed at the end of each period. Results In arm 1, comparing period 3 to period 1, the geometric mean ratio (GMR) for the 24-hour area under the time-concentration curve (AUC0-24) was 1.33 [90% confidence interval (CI): 1.14 to 1.53], and the GMR for the trough (Cτ) was 1.22 (90% CI: 1.01 to 1.48). Comparing period 2 to period 1 in arm 2, the GMR for the AUC0-24 was 0.95 (90% CI: 0.82 to 1.10), and the GMR for the Cτ was 0.70 (90% CI: 0.57 to 0.87). Conclusions Regimens including twice-daily DTG and RIF or once-daily DTG and RBT may represent a new treatment option for patients who require concomitant treatment of HIV and TB.

Summary Background Dolutegravir (S/GSK1349572) is a new HIV-1 integrase inhibitor that has antiviral activity with once daily, unboosted dosing. SPRING-1 is an ongoing study designed to select a dose for phase 3 assessment. We present data from preplanned primary and interim analyses. Methods In a phase 2b, multicentre, dose-ranging study, treatment-naive adults were randomly assigned (1:1:1:1) to receive 10 mg, 25 mg, or 50 mg dolutegravir or 600 mg efavirenz. Dose but not drug allocation was masked. Randomisation was by a central integrated voice-response system according to a computer-generated code. Study drugs were given with either tenofovir plus emtricitabine or abacavir plus lamivudine. Our study was done at 34 sites in France, Germany, Italy, Russia, Spain, and the USA beginning on July 9, 2009. Eligible participants were seropositive for HIV-1, aged 18 years or older, and had plasma HIV RNA viral loads of at least 1000 copies per mL and CD4 counts of at least 200 cells per μL. Our primary endpoint was the proportion of participants with viral load of less than 50 copies per mL at week 16 and we present data to week 48. Analyses were done on the basis of allocation group and included all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00951015. Findings 205 patients were randomly allocated and received at least one dose of study drug: 53, 51, and 51 to receive 10 mg, 25 mg, and 50 mg dolutegravir, respectively, and 50 to receive efavirenz. Week 16 response rates to viral loads of at most 50 copies per mL were 93% (144 of 155 participants) for all doses of dolutegravir (with little difference between dose groups) and 60% (30 of 50) for efavirenz; week 48 response rates were 87% (139 of 155) for all doses of dolutegravir and 82% (41 of 50) for efavirenz. Response rates between nucleoside reverse transcriptase inhibitor subgroups were similar. We identified three virological failures in the dolutegravir groups and one in the efavirenz group—we did not identify any integrase inhibitor mutations. We did not identify any dose-related clinical or laboratory toxic effects, with more drug-related adverse events of moderate-or-higher intensity in the efavirenz group (20%) than the dolutegravir group (8%). We did not judge that any serious adverse events were related to dolutegravir. Interpretation Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses. Our findings support the assessment of once daily 50 mg dolutegravir in phase 3 trials. Funding Shionogi-GlaxoSmithKline Pharmaceuticals, LLC, now Shionogi-ViiV Healthcare, LLC.

AIMS S/GSK1349572 is an unboosted, once daily, next generation integrase inhibitor with potent activity, low pharmacokinetic (PK) variability and a novel resistance profile. As the primary route of metabolism is via glucuronidation, the effects of atazanavir (ATV, a UGT1A1 inhibitor) and atazanavir/ritonavir (ATV/RTV) on S/GSK1349572 PK were evaluated.

Objectives: To evaluate the effect of pH-altering agents on S/GSK1349572 exposure in healthy subjects. Methods: S/GSK1349572 is an unboosted, once-daily, next-generation HIV integrase inhibitor. In the first study, 16 subjects received four single-dose treatments: (i) S/GSK1349572 50 mg; (ii) S/GSK1349572 50 mg with a multivitamin (MVI; One A Day Maximum); (iii) S/GSK1349572 50 mg with a liquid antacid (Maalox Advanced Maximum Strength); and (iv) S/GSK1349572 50 mg 2 h before an antacid. In the second study, 12 subjects received a single dose of S/GSK1349572 alone and on day 5 of omeprazole. Results: All treatments were well tolerated. MVI co-administration modestly decreased S/GSK1349572 AUC by 33%. Concurrent antacid co-administration reduced S/GSK1349572 AUC by 74% and staggered antacid dosing significantly diminished this interaction, with a reduction in S/GSK1349572 AUC of 26%. Omeprazole did not significantly affect S/GSK1349572 exposure. Conclusions: S/GSK1349572 can be taken with proton pump inhibitors and MVIs without dose adjustment but should be administered 2 h before or 6 h after antacids.

S/GSK1349572 is a novel integrase inhibitor with potent in vitro anti-HIV activity, an in vitro resistance profile different from those of other integrase inhibitors, and favorable preclinical safety and pharmacokinetics (PK). Randomized, double-blind, placebo-controlled single-dose and multiple-dose, dose escalation studies evaluated the PK, safety, and tolerability of S/GSK1349572 for healthy subjects. In the single-dose study, two cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 2, 5, 10, 25, 50, and 100 mg in an alternating panel design. In the multiple-dose study, three cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 10, 25, and 50 mg once daily for 10 days. A cytochrome P450 3A (CYP3A) substudy with midazolam was conducted with the 25-mg dose. Laboratory testing, vital signs, electrocardiograms (ECGs), and PK sampling were performed at regular intervals. S/GSK1349572 was well tolerated. Most adverse events (AEs) were mild, with a few moderate AEs reported. Headache was the most common AE. No clinically significant laboratory trends or ECG changes were noted. PK was linear over the dosage range studied. The steady-state geometric mean area under the concentration-time curve over a dosing interval (AUC 0-τ ) and maximum concentration of the drug in plasma ( C max ) ranged from 16.7 μg·h/ml (coefficient of variation [CV], 15%) and 1.5 μg/ml (CV, 24%) at a 10-mg dose to 76.8 μg·h/ml (CV, 19%) and 6.2 μg/ml (CV, 15%) at a 50-mg dose, respectively. The geometric mean steady-state concentration at the end of the dosing interval ( C τ ) with a 50-mg dose was 1.6 μg/ml, approximately 25-fold higher than the protein-adjusted 90% inhibitory concentration (0.064 μg/ml). The half-life was approximately 15 h. S/GSK1349572 had no impact on midazolam exposure, indicating that it does not modulate CYP3A activity. The PK profile suggests that once-daily, low milligram doses will achieve therapeutic concentrations.

Abacavir (ABC) is administered either at 600 mg once daily (ABC 600 mg QD) or 300 mg twice daily (ABC 300 mg BID) in anti-human immunodeficiency virus (anti-HIV) combination therapy. Although ABC plasma pharmacokinetics following each regimen has been well defined, no study has directly compared the regimens with respect to pharmacokinetics of ABC's active intracellular anabolite, carbovir-triphosphate (CBV-TP). In an open-label, two-period, crossover study, 34 HIV-infected male and female subjects stabilized on antiretroviral regimens containing either ABC 600 mg QD or ABC 300 mg BID received their usual doses on days −1 and 1 and then switched regimens for days 2 to 11. Serial blood samples collected on days 1 and 11 were assayed for plasma ABC and intracellular CBV-TP concentrations using validated high-performance liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods. Analysis of variance with a mixed-effect model was performed for treatment and gender comparisons. In 27 evaluable subjects, the regimens provided bioequivalent ABC daily areas under the concentration-time curve from 0 to 24 h (AUC 0-24 ) and comparable CBV-TP concentrations at the end of the dosing interval ( C τ ). As expected, ABC QD resulted in 109% higher ABC maximum concentrations of drug in plasma ( C max ) than did ABC BID. ABC QD also resulted in 32% higher CBV-TP AUC 0-24 and 99% higher CBV-TP C max than did ABC BID. Females had a 38% higher weight-adjusted ABC AUC 0-24 and 81% higher weight-adjusted CBV-TP AUC 0-24 than did males. Virologic suppression was maintained during regimen switch, and no tolerability differences between regimens were observed. In conclusion, this study showed that ABC 600 mg QD and ABC 300 mg BID regimens led to similar intracellular CBV-TP C τ values, thus providing pharmacokinetic support for the interchangeability of these two regimens. Women had higher intracellular CBV-TP exposure than did men.

GSK364735 is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor with potent in vitro antiviral activity. This study was a double-blind, randomized, placebo-controlled, dose escalation, phase I study to assess single- and repeated-dose safety, tolerability, pharmacokinetics (PK), and food effect of GSK364735 in healthy subjects. In part A, three alternating cohorts of 10 subjects (8 receiving the active drug and 2 receiving a placebo) received single doses of 50 to 400 mg while fasting or 200 mg and 400 mg coadministered with food. In part B, five cohorts received repeated doses of 100 to 600 mg daily coadministered with food for 8 days. Safety was assessed throughout the study. Serial blood samples were analyzed for GSK364735 plasma concentrations using a validated high-performance liquid chromatography-tandem mass spectrometry assay. PK parameters were estimated using noncompartmental methods. Seventy-nine (30 in part A and 49 in part B) subjects were enrolled and received GSK364735 or placebo. GSK364735 was readily absorbed following oral dose administration, with the maximum concentration achieved between 0.75 to 5.0 h postdose. GSK364735 exposure increased less than dose proportionally, demonstrated wide variability, and appeared to reach a plateau at 100- to 200-mg doses. Food increased GSK364735 exposure by 28 to 91%. GSK364735 was safe and well tolerated after single- and repeated-dose administration. No serious or severe adverse events (AEs) or AEs leading to withdrawal and few drug-related AEs were reported. Despite solubility-limited absorption, GSK364735 exceeded therapeutic trough concentrations for the majority of doses studied. The PK and safety profile supported the continued investigation of GSK364735 in HIV-infected subjects.

Aplaviroc is a novel CCR5 antagonist, a class of compounds under investigation as viral entry inhibitors for the treatment of human immunodeficiency virus infection. A modified Cooperstown 5 +1 cocktail was used to assess the drug interaction potential of aplaviroc. Fifteen healthy subjects were administered single oral doses of caffeine (CYP1A2), warfarin (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A) alone (reference treatment) and during steady-state administration of aplaviroc (400 mg every 12 hours, test treatment). Metabolite-to-parent area under the plasma concentration versus time curve (AUC) ratios (paraxanthine/caffeine and 5-hydroxyomeprazole/omeprazole), oral clearance (S-warfarin), AUC (midazolam), and metabolite-to-parent urinary excretion ratio (dextrorphan/dextromethorphan) were determined. The test-to-reference treatment ratios (geometric mean ratio and 90% confidence interval) were caffeine, 1.06 (0.97–1.17); S-warfarin, 0.93 (0.76–1.15); omeprazole, 1.07 (0.98–1.16); dextromethorphan, 1.17 (0.97–1.42); midazolam, 1.30 (1.04–1.63). No significant inhibition of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 enzyme activity was observed. Mild inhibition of CYP3A isozymes should not preclude the use of concomitant CYP3A substrates in future clinical studies with aplaviroc.

Propranolol is a noncardioselective beta-adrenergic antagonist that has been recently reported to prolong the QTc interval on the surface electrocardiogram in humans when overdosed [Farhangi, V., Sansone, R.A. (2003). QTc prolongation due to propranolol overdose. Int. J. Psychiatry Med. 33, 201-202.]. To examine the underlying mechanisms for these clinical findings, we studied the effects of propranolol on the human cardiac potassium channels encoded by the ether-a-go-go-related gene (ERG) using the whole cell voltage-clamp technique. We found that propranolol blocked hERG currents in a concentration-dependent manner with an IC50 of 9.9+/-1.3 microM which is relevant to the predicted plasma level of propranolol in this case report. The present study demonstrated that propranolol can inhibit hERG channels. The interaction between propranolol and hERG channels could lead to delayed cardiac repolarization and might be a molecular mechanism for the previously reported QTc prolongation when propranolol is overdosed.

Dolutegravir (DTG) is an HIV integrase inhibitor (INI) with demonstrated activity in INI-naive and INI-resistant patients. The objective of this open-label, 2-period, single-sequence study was to evaluate the effect of fosamprenavir-ritonavir (FPV-RTV) on the steady-state plasma pharmacokinetics of DTG. Twelve healthy subjects received 50 mg DTG once daily for 5 days (period 1), followed by 10 days of 50 mg DTG once daily in combination with 700/100 mg FPV-RTV every 12 h (period 2). All doses were administered in the fasting state. Serial pharmacokinetic samples for DTG and amprenavir and safety assessments were obtained throughout the study. Noncompartmental pharmacokinetic analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated for within-subject treatment comparison. Fosamprenavir-ritonavir decreased the DTG area under the concentration-time curve, maximum concentration in plasma, and concentration in plasma at the end of the dosing interval by 35%, 24%, and 49%, respectively. Both DTG and DTG with FPV-RTV were well tolerated; no subject withdrew because of adverse events. The most frequently reported drug-related adverse events were rash, abnormal dreams, and nasopharyngitis. The modest decrease in DTG exposure when it was coadministered with FPV-RTV is not considered clinically significant, and DTG dose adjustment is not required with coadministration of FPV-RTV in INI-naive patient populations on the basis of established “no-effect” boundaries of DTG. In the INI-resistant population, as a cautionary measure, alternative combinations that do not include FPV-RTV should be considered. (This study has been registered at ClinicalTrials.gov under identifier NCT01209065.)

Purpose Dolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects. Methods The first study was an open-label crossover where 12 subjects received DTG 50 mg every 24 hours (q24h) for 5 days, followed by DTG 50 mg and EFV 600 mg q24h for 14 days. The second study was an open-label crossover where 18 subjects received DTG 50 mg q24h for 5 days followed by TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further 5 days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90 % confidence intervals were generated. Results The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75 % in DTG AUC(0–τ), Cmax and Cτ, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76 % in DTG AUC(0–τ), Cmax and Cτ, respectively. Conclusions Given the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50 mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients. Electronic supplementary material The online version of this article (doi:10.1007/s00228-014-1732-8) contains supplementary material, which is available to authorized users.

Background: The potential for a drug interaction between S/GSK1349572 and tenofovir disoproxil fumarate (TDF) was evaluated in an open-label, repeat dose, 3-period, drug-drug interaction study in healthy subjects. Methods: S/GSK1349572 was administered at 50 mg once daily for 5 days (period 1) followed by a 6-day washout period. TDF 300 mg once daily was then administered for 7 days (period 2). The combination of S/GSK1349572 and TDF was then coadministered for 5 days (period 3). Pharmacokinetic parameters were determined and compared between periods. Results: Fifteen subjects completed all periods and follow-up. S/GSK1349572 and TDF were generally well tolerated with few adverse events reported. No clinically significant trends in post-dose laboratory abnormalities, vital signs, or electrocardiogram values were noted. Pharmacokinetic parameters of S/GSK1349572 and tenofovir during combination therapy were similar to those when given alone, demonstrating no significant drug interaction. S/GSK1349572 geometric least squares mean ratios (90% confidence interval) for AUC(0-τ), C max , and C τ were 1.01 (0.908, 1.11), 0.969 (0.867, 1.08), and 0.920 (0.816, 1.04), respectively. Tenofovir geometric least squares mean ratios (90% confidence interval) for AUC(0-τ), C max , and C τ were 1.12 (1.01, 1.24), 1.09 (0.974, 1.23), and 1.19 (1.04, 1.35), respectively. Conclusion: S/GSK1349572 and TDF can be coadministered without dose adjustment.

Aim: To evaluate potential pharmacogenetic effects of UGT1A1 polymorphisms on the pharmacokinetics (PK) of dolutegravir (Tivicay®; ViiV Healthcare, NC, USA), an HIV-1 integrase inhibitor. Patients & methods: Analysis of pooled data from nine Phase I and II clinical studies was undertaken for 89 subjects receiving repeat dolutegravir 50 mg once daily (tablet formulation) who were genotyped for known UGT1A1 functional variants. Results: Geometric mean ratio (92% CI) for subjects carrying low (*28/*28 and *28/*37) and reduced activity (*1/*6, *1/*28, *1/*37, *28/*36 and *36/*37) polymorphisms compared with subjects with normal activity (*1/*1 and *1/*36) showed decreased oral clearance (CL/F; 0.765 [92% CI: 0.659–0.889]), increased area under the concentration–time curve (AUC0-τ; 1.307 [1.125–1.518]) and Cmax (1.221 [1.063–1.402]), respectively. Conclusion: Increased dolutegravir exposure in carriers of UGT1A1 reduced function polymorphisms is not clinically significant based on accumulated safety data so dose adjustment in these individuals is not required.

Background This study evaluated the pharmacokinetics of a granule formulation of dolutegravir developed as an alternative to tablets for use in paediatric populations. Methods A randomized, open-label study in healthy adults was carried out. Subjects received five treatments in a crossover design: a single dose of dolute-gravir 50 mg as a tablet and dolutegravir 50 mg in 10 g of granule administered directly to mouth or mixed with purified water, water containing high cation concentrations or milk-based infant formula. Study treatments were separated by 7 days. Safety evaluations and serial pharmacokinetic sampling were done during each treatment period. A non-compartmental pharmacokinetic analysis was performed; geometric least-squares mean ratios and 90% CIs were generated for treatment comparison. Palatability was assessed by questionnaire. Results Plasma dolutegravir exposures in all granule treatment arms exceeded those of tablet formulation. The mean area under the curve from time 0 to infinity (AUC0–∞) and maximum concentrations were 55–83% and 62–102% higher, respectively. Pharmacokinetics were similar when dolutegravir was mixed with purified or cation-containing water. Dolutegravir was well tolerated, with no withdrawals due to adverse events. Taste was rated acceptable for all treatments. Conclusions The exposure of dolutegravir after administration of granule formulation alone, with different types of water and with milk formula, exceeded that of the tablet. The similarity of dolutegravir exposure seen with the granule formulation demonstrates that dolutegravir granule can be given without restriction on the type of liquid or can be administered directly to the mouth (for example, when potable water is not available).

Background Dolutegravir (DTG) is an investigational integrase inhibitor for treatment of HIV infection. As intravenous drug use is a common risk factor for HIV, this study evaluated the effect of DTG on the pharmacokinetics (PK) of methadone. Methods This was an open-label, 2-period study in adult, opioid-dependent, HIV-seronegative subjects. Subjects received their current individual methadone doses once daily for 3 days (Period 1) followed by DTG 50 mg twice daily (BID) for 5 days while continuing their stable methadone therapy (Period 2). Serial PK samples for R- and S-methadone were collected after each Period. Pharmacodynamic (PD) measures and safety assessments were obtained throughout the study. Non-compartmental PK analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated. Results Plasma exposures of total, R-, and S-methadone were not affected by co-administration of DTG. Mean ratios for AUC were 0.98, 0.95, and 1.01 for total, R-, and S-methadone, respectively, alone compared with in combination with DTG. No statistically significant differences were noted between the 2 treatment periods in methadone PD measures. The combination of DTG and methadone was well tolerated. No deaths, serious adverse events, or grade 3/4 adverse events occurred. No clinically significant changes in laboratory values, vital signs, or electrocardiograms were observed. Conclusion Co-administration of methadone with repeat doses of DTG 50 mg BID had no effect on total, R-, and S-methadone PK or on methadone-induced PD markers. No dose adjustment in methadone is required when given in combination with DTG.

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.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.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.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.

Study Objective To assess the effect of a supratherapeutic dose of the integrase inhibitor dolutegravir on the QT and corrected QT (QTc) interval. Design Randomized, partial-blind, placebo-controlled, single-dose, 3-period, balanced crossover study. Setting Clinical research unit. Subjects Forty-two healthy subjects were randomized; of these subjects, 38 completed the study, three withdrew early because of protocol violations, and one was lost to follow-up. Intervention Subjects were randomized to receive three single doses of the following treatments: dolutegravir 250-mg suspension, moxifloxacin 400-mg tablet, and placebo suspension; each treatment was separated by a 14-day washout period. Treatment with the dolutegravir and placebo suspension was blinded, whereas treatment with moxifloxacin was open label. Measurements and Main Results The pharmacokinetic exposure at a supratherapeutic dose of dolutegravir 250 mg was 2–4 times higher than the pharmacokinetic exposure at clinically relevant dosages (50 mg once or twice/day). The upper limit of the 90% confidence interval (CI) for the placebo-adjusted mean change from baseline of the QTc interval (ΔΔQTcF) using Fridericia's formula was less than 10 msec at all time points. The sensitivity of the study to detect modest increases in QT interval was established with moxifloxacin, a positive control for QT-interval prolongation. The maximum ΔΔQTcF values for dolutegravir and moxifloxacin were observed at 4 hours: 1.99 msec (90% CI −0.55–4.53 msec) and 9.58 msec (90% CI 7.05–12.11 msec), respectively. Conclusion This pharmacokinetic-pharmacodynamic model demonstrates no relationship between dolutegravir plasma concentration and ΔΔQTcF. Furthermore, a supratherapeutic dose of dolutegravir was generally well tolerated without any serious or severe adverse events. As such, dolutegravir does not affect cardiac repolarization.

Dolutegravir (DTG) is an unboosted, once-daily integrase inhibitor currently in phase 3 trials. Two studies evaluated the effects of etravirine (ETR) alone and in combination with ritonavir (RTV)-boosted protease inhibitors (PIs) on DTG pharmacokinetics (PK) in healthy subjects. DTG 50 mg every 24 h (q24h) was administered alone for 5 days in period 1, followed by combination with ETR at 200 mg q12h for 14 days in period 2 (study 1) or with ETR/lopinavir (LPV)/RTV at 200/400/100 mg q12h or ETR/darunavir (DRV)/RTV at 200/600/100 mg q12h for 14 days in period 2 (study 2). PK samples were collected on day 5 in period 1 and day 14 in period 2. All of the treatments were well tolerated. ETR significantly decreased exposures of DTG, with geometric mean ratios of 0.294 (90% confidence intervals, 0.257 to 0.337) for the area under the curve from time zero until the end of the dosage interval (AUC 0-τ ), 0.484 (0.433 to 0.542) for the observed maximum plasma concentration ( C max ), and 0.121 (0.093 to 0.157) for the plasma concentration at the end of the dosage interval ( C τ ). ETR combined with an RTV-boosted PI affected the exposure of DTG to a lesser degree: ETR/LPV/RTV treatment had no effect on the DTG plasma AUC 0-τ and C max , whereas the C τ increased by 28%. ETR/DRV/RTV modestly decreased the plasma DTG AUC 0-τ , C max , and C τ by 25, 12, and 37%, respectively. Such effects of ETR/LPV/RTV and ETR/DRV/RTV are not considered clinically relevant. The combination of DTG and ETR alone should be avoided; however, DTG may be coadministered with ETR without a dosage adjustment if LPV/RTV or DRV/RTV is concurrently administered.

Objective: To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of dolutegravir (DTG), a next-generation HIV integrase inhibitor (INI), as short-term monotherapy. Design: A phase IIa, randomized, double-blind, dose-ranging study. Methods: In this study, INI-naive, HIV-1-infected adults currently off antiretroviral therapy were randomized to receive DTG (2, 10, or 50mg) or placebo once daily for 10 days in an eight active and two placebo randomization scheme per DTG dose. Placebo patients were pooled for the purpose of analysis. Results: Thirty-five patients (n ¼9 for DTG 2 and 10mg, n ¼10 for DTG 50mg, and n ¼7 for placebo) were enrolled. Baseline characteristics were similar across dosegroups.SignificantreductionsinplasmaHIV-1RNAfrombaselinetoday11were observed for all DTG dose groups compared with placebo (P

S/GSK1349572 is an unboosted, once daily, next generation integrase inhibitor with potent activity, low pharmacokinetic (PK) variability and a novel resistance profile. As the primary route of metabolism is via glucuronidation, the effects of atazanavir (ATV, a UGT1A1 inhibitor) and atazanavir/ritonavir (ATV/RTV) on S/GSK1349572 PK were evaluated.A randomized, open label, two period, crossover study was conducted in healthy adult subjects. Twenty-four subjects received S/GSK1349572 30 mg every 24 h for 5 days. Subjects then were administered S/GSK1349572 30 mg every 24 h in combination with either ATV/RTV 300/100 mg every 24 h (n= 12) or ATV 400 mg every 24 h (n= 12) for 14 days. Serial PK samples and safety assessments were obtained throughout the study.The combination of S/GSK1349572 with ATV/RTV or ATV was generally well tolerated. All adverse events were mild or moderate, and no subject withdrew because of an adverse event. The AE of highest frequency was ocular icterus, observed only during combination of S/GSK1349572 and ATV or ATV/RTV. Co-administration with ATV/RTV resulted in increased plasma S/GSK1349572 area under the concentration-time curve during a dosing interval (AUC(0,τ)), observed maximal concentration (C(max) ), and concentration at the end of dosing interval at steady state (C(τ) ) by 62%, 34% and 121%, respectively. Co-administration with ATV resulted in increased plasma S/GSK1349572 AUC(0,τ), C(max) , and C(τ) by 91%, 50% and 180%, respectively.Co-administration of ATV/RTV and ATV was generally well tolerated and produced a modest, non-clinically significant increase in S/GSK1349572 exposure. No dose adjustment for S/GSK1349572 is necessary when co-administered with ATV and ATV/RTV.

S/GSK1349572 is an unboosted, once-daily integrase inhibitor with a novel resistance profile. As standard of care for patients infected with HIV is combination therapy, the potential interaction between S/GSK1349572 and ritonavir-boosted protease inhibitors was evaluated. In an open-label, repeat-dose, 2-period, 2-sequence crossover study in healthy participants, S/GSK1349572 was administered at 30 mg once daily for 5 days, followed by randomization to lopinavir/ritonavir 400/100 mg twice daily or darunavir/ritonavir 600/100 mg twice daily coadministered with S/GSK1349572 30 mg once daily for 14 days. There was no washout between periods. Serial pharmacokinetic (PK) samples and safety assessments were obtained throughout the study. Thirty of 31 participants completed the study (15 participants per group). Treatment comparisons of steady-state S/GSK1349572 PK parameters demonstrated that coadministration of lopinavir/ritonavir had no significant effect on steady-state PK of S/GSK1349572. Coadministration of darunavir/ritonavir resulted in a nonclinically significant reduction in steady-state plasma S/GSK1349572 exposures. Plasma S/GSK1349572 AUC((0-τ)), C(max), and C(τ) decreased by 22%, 11%, and 38%, respectively, on average. S/GSK1349572 was well tolerated with no serious adverse events (AEs) or withdrawals due to drug-related AEs. The most frequent drug-related AEs were diarrhea, dizziness, and headache. No dosage adjustment for S/GSK1349572 is required when used with lopinavir/ritonavir or darunavir/ritonavir.

Introduction : Dolutegravir (DTG) is an HIV integrase strand transfer inhibitor approved for use in combination with other antiretrovirals for the treatment of HIV-infection in adults and adolescents. Metformin is a drug frequently used in diabetic HIV-infected patients, which requires titration to optimize dosing. In vitro , DTG inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE 1) which are known to be involved in the disposition of metformin. The objective of this study was to assess the drug interaction between DTG and metformin. Materials and Methods : This was an open-label, parallel-group, three-period crossover study in healthy adult subjects. Eligible subjects were enrolled into one of the two treatment cohorts (15 subjects/cohort). Subjects received metformin 500 mg q12h for 5 days in Period 1; metformin 500 mg q12h plus DTG 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. All doses of study drug were taken with a moderate-fat meal. Serial plasma PK samples and safety assessments were obtained throughout the study. Non-compartmental PK analysis was performed and geometric least squares (GLS) mean ratios and 90% confidence intervals (CI) were generated by the mixed effect model for within-subject treatment comparisons for each cohort. Results : Fourteen and thirteen subjects completed study in Cohort 1 and Cohort 2, respectively. Plasma exposures of metformin were significantly increased when co-administered with DTG (Table 1). There were no apparent changes in metformin half-life and tmax. Increased metformin plasma exposure returned to normal levels observed in Period 1 after DTG was discontinued in Period 3. No Grade 3 or 4 adverse events (AEs), deaths or serious AEs were reported during the study. Most frequently reported drug-related AEs were headache (9), loose stools (8), and nausea (7). All AEs were mild or Grade 1 with the exception of one Grade 2 headache. Conclusions : Co-administration of DTG and metformin was well tolerated, yet significantly increased metformin plasma exposure; effects were DTG dose dependent. Though metformin has a wide therapeutic index and alone is not associated with hypoglycemia, close monitoring is recommended when co-administering metformin and DTG. Dose adjustments of metformin may be considered. (Published: 2 November 2014) Citation : Abstracts of the HIV Drug Therapy Glasgow Congress 2014 Zong J et al. Journal of the International AIDS Society 2014, 17(Suppl 3) :19584 http://www.jiasociety.org/index.php/jias/article/view/19584 | http://dx.doi.org/10.7448/IAS.17.4.19584

In the VIKING study a 50 mg once daily regimen of the next generation HIV integrase inhibitor (INI) S/GSK1349572 (572) exhibited promising antiviral activity in an initial cohort (Cohort I) of treatment-experienced subjects with documented raltegravir (RAL) resistance. The purpose of this work was to evaluate via simulation techniques whether improved virologic responses could be achieved with higher doses in a second cohort (Cohort II) by utilizing pharmacokinetic (PK) and pharmacodynamic (PD) models derived using Cohort I data. Interim PK data from VIKING Cohort I were combined with data from Phase 1 and 2a studies in healthy and HIV+, INI-naive subjects, respectively; data were analyzed using a linear two-compartment PK model. The population PK/PD analysis incorporated log10 HIV-1 RNA viral load (VL) sampled throughout 10 days of dosing during the Phase 2a and VIKING studies. The VL was modelled using an indirect response model in which the 572 plasma concentrations inhibited HIV-1 RNA production. Final PK and PK/PD models were validated using the visual predictive check (VPC) technique. Two sets of simulations were used to predict responder percentage for dose regimens proposed for Cohort II of VIKING. First, change from baseline in log10 VL (ΔVL) at Day 11 was simulated for cohorts of 1000 subjects for each dose regimen according to different fixed levels of baseline fold change (FC) in 572 IC50 from wild type virus. The second set of simulations predicted responder percentages for clinical RAL-resistant HIV populations with diverse 572 susceptibilities. The data were well-described by the respective models. Model parameters were generally well-determined and VPC plots verified predictive performance. Simulations predicted increasing the dose regimen from 50 mg once daily to 50 mg twice daily would increase the percentage of patients with FC=8 that achieved ≥ 1.5 log10 ΔVL at Day 11 by ~28%. Similarly, improvements in response of ~20% and ~18% were predicted for patient populations with HIV resistance profiles observed in RAL PhIIb and BENCHMRK virologic failure and VIKING screening populations, respectively. Our models predict 572 50mg twice daily will appreciably increase Day11 virologic responses in RAL-resistant subjects, supporting the dosing strategy for the ongoing Cohort II. 572 shows promise to demonstrate further the activity in this difficult to treat patient population.

Daclatasvir (DCV) is an NS5A replication complex inhibitor recently approved for chronic hepatitis C virus treatment. 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. 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. 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. Registered on March 6, 2014 with ClinicalTrials.gov; registration number: NCT02082808 and as Study ID: 201102 on the ViiV Clinical Study Registry.