Clinical Bridging Studies and Modeling Approach for Implementation of a Patient Centric Sampling Technique in Padsevonil Clinical Development.

Volumetric absorptive microsampling (VAMS) techniques have gained popularity these last years as innovative tool for collection of blood pharmacokinetic (PK) samples in clinical trials as they offer many advantages over dried blood spot and conventional venous blood sampling. The use of Mitra®, a blood collection device based on volumetric absorptive microsampling (VAMS) technology, was implemented during clinical development of padsevonil (PSL), an anti-seizure medication (ASM) candidate. The present study describes the approach used to bridge plasma (obtained from conventional venous blood sampling) and blood exposures (obtained with Mitra®) to support the use of Mitra as sole blood PK sampling method in clinical trials. Paired blood (using Mitra®) and plasma samples (using conventional venous blood sampling) were collected in healthy volunteers as well as in patients with epilepsy. PSL concentration in plasma and blood were analyzed using different approaches which included evaluation of blood-to-plasma ratios (B/P) over time, linear regression, Bland-Altman analysis as well as development of a linear-mixed effect model based on clinical pharmacology studies. Results showed that the observed in vivo B/P and the measured bias between the 2 collection methods were consistent with the measured in vitro B/P. Graphical analysis demonstrated a clear time effect on the B/P which was confirmed in the linear mixed effect model with sampling time identified as significant covariate. Finally, the built-in model was validated using independent datasets and was shown to adequately predict plasma concentration based on blood concentration with a mean bias of less than 9% (predicted versus observed plasma concentration).

Switching at Low HIV-1 RNA into Fixed Dose Combinations: TDF/FTC/RPV is non-inferior to TDF/FTC/EFV in first-line suppressed patients living with HIV.

BACKGROUND: In low- and middle-income countries (LMICs), a substantial unmet need for affordable single-tablet regimen (STR) options remains. Rilpivirine (RPV, TMC278) is formulated in a low-cost STR with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). OBJECTIVES: Switching at Low HIV-1 RNA into Fixed Dose Combinations (SALIF) compared RPV with efavirenz (EFV), both as STRs with TDF and FTC, in maintaining virologic suppression. METHODS: SALIF was a phase 3b, randomised, open-label, non-inferiority study in virologically suppressed adults (HIV-1 RNA < 50 copies/mL) on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) in Cameroon, Kenya, Senegal, South Africa, Uganda and Thailand. Patients (N = 426), stratified by NNRTI use, were randomised 1:1 to receive TDF/FTC/RPV (300/200/25 mg qd) or TDF/FTC/EFV (300/200/600 mg qd). Primary endpoint was proportion of patients with virologic suppression (HIV-1 RNA < 400 copies/mL) at week 48 (intent-to-treat, modified Food and Drug Administration Snapshot, 10% non-inferiority margin). RESULTS: Patients received TDF/FTC/RPV (n = 213) or TDF/FTC/EFV (n = 211). At week 48, virologic suppression was maintained in 200/213 (93.9%) patients in the RPV arm and 203/211 (96.2%) in the EFV arm (difference -2.3%; 95% confidence interval: -6.4, +1.8), demonstrating non-inferiority of TDF/FTC/RPV. One patient in each arm experienced virologic failure without treatment-emergent resistance. Twenty-seven patients discontinued prematurely (8.0% RPV vs. 4.7% EFV), the most frequent reasons being adverse events (3.3% vs. 0.5%, respectively), site closure (1.9% vs. 0.5%), loss to follow-up (0.9% vs. 1.4%) and consent withdrawal (0.9% vs. 1.4%). CONCLUSION: In adults with suppressed viral load on first-line NNRTI-based ART in LMICs, switching to an STR of TDF/FTC/RPV was non-inferior to TDF/FTC/EFV in maintaining high rates of viral suppression with a comparable tolerability profile.

Impact of Splitting or Crushing on the Relative Bioavailability of the Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is an oral once-daily single-tablet regimen for the treatment of human immunodeficiency virus-1 infection. Different administration modalities for the D/C/F/TAF fixed-dose combination tablet were explored in this phase 1 randomized, open-label, 3-period, 3-treatment crossover study enrolling 30 healthy adults. The primary objective was to assess the relative bioavailability of each component after a single dose of D/C/F/TAF (800/150/200/10 mg) administered as a split or crushed tablet (tests) versus swallowed whole (reference). Pharmacokinetic parameters (noncompartmental analysis; logarithm-transformed) for each component were compared using linear mixed-effects modeling. For the split versus whole tablet, the bioavailabilities (maximum plasma concentration [Cmax ] and area under the plasma concentration-time curve [AUClast ]) of each D/C/F/TAF component were comparable. For the crushed versus whole tablet, the bioavailabilities of darunavir, cobicistat, and emtricitabine were comparable, except for a 17% decrease in emtricitabine Cmax ; the relative bioavailability of tenofovir alafenamide decreased by 29% and 19% for Cmax and AUClast , respectively. All intakes were safe and generally well tolerated. In summary, there was no clinically relevant impact on the bioavailability of D/C/F/TAF components when administered as a split tablet compared with a tablet swallowed whole. Administration of a crushed tablet resulted in a modest decrease in tenofovir alafenamide bioavailability; the clinical relevance of this change has not been assessed but is expected to be minimal based on the wide therapeutic window for this agent.

Pharmacokinetics, Antiviral Activity, and Safety of Rilpivirine in Pregnant Women with HIV-1 Infection: Results of a Phase 3b, Multicenter, Open-Label Study.

INTRODUCTION: Physiologic changes during pregnancy may impact the pharmacokinetics of drugs. In addition, efficacy and safety/tolerability concerns have been identified for some antiretroviral agents. METHODS: Human immunodeficiency virus (HIV)-1-infected pregnant women (18-26 weeks gestation) receiving the non-nucleoside reverse transcriptase inhibitor rilpivirine 25 mg once daily were enrolled in this phase 3b, open-label study examining the impact of pregnancy on the pharmacokinetics of rilpivirine when it is given in combination with other antiretroviral agents. Blood samples (collected over the 24-h dosing interval) to assess total and unbound rilpivirine plasma concentrations were obtained during the second and third trimesters (24-28 and 34-38 weeks gestation, respectively) and 6-12 weeks postpartum. Pharmacokinetic parameters were derived using noncompartmental analysis and compared (pregnancy versus postpartum) using linear mixed effects modeling. Antiviral and immunologic response and safety were assessed. RESULTS: Nineteen women were enrolled; 15 had evaluable pharmacokinetic results. Total rilpivirine exposure was 29-31% lower during pregnancy versus postpartum; differences were less pronounced for unbound (pharmacodynamically active) rilpivirine. At study entry, 12/19 (63.2%) women were virologically suppressed; 10/12 (83.3%) women were suppressed at the postpartum visit. Twelve infants were born to the 12 women who completed the study (7 discontinued); no perinatal viral transmission was observed among 10 infants with available data. Rilpivirine was generally safe and well tolerated in women and infants exposed in utero. CONCLUSION: Despite decreased rilpivirine exposure during pregnancy, treatment was effective in preventing mother-to-child transmission and suppressing HIV-1 RNA in pregnant women. Results suggest that rilpivirine 25 mg once daily, as part of individualized combination antiretroviral therapy, may be an appropriate option for HIV-1-infected pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT00855335.

Clinical impact of pharmacokinetic interactions between the HCV protease inhibitor simeprevir and frequently used concomitant medications.

AIMS: Direct-acting antiviral agents (DAAs) for the treatment of hepatitis C (HCV) can be associated with drug-drug interactions (DDIs) with concomitant medications. The practical clinical implications of such DDIs are poorly understood. We assessed the clinical impact of possible pharmacokinetic (PK) interactions between simeprevir and frequently prescribed concomitant medications. METHODS: This post hoc analysis pooled data from nine studies which evaluated simeprevir (SMV)-based interferon-free HCV treatment. Three classes of frequently used concomitant medications of interest (CMOIs) were analysed [antihypertensive drugs (AHDs), anxiolytic drugs (AXDs) and lipid-lowering drugs (LLDs)] and categorized as amber or green according to their DDI potential with SMV (green: no DDIs; amber: potential/known PK interactions). Concomitant medications not recommended to be coadministered with SMV were not included. The composite primary endpoint was defined as the frequency of either discontinuation, interruption or dose modification of the CMOI during 12 weeks of SMV treatment. RESULTS: Few patients met the composite endpoint in the various subgroups. Patients on amber CMOIs tended to experience CMOI modification more often (13.4-19.4%) than those on green CMOIs (3.1-10.8%). There was no difference in the frequency of adverse events between patients taking green and those taking amber CMOIs. CONCLUSIONS: In this large pooled analysis, coadministration of the evaluated commonly prescribed medications with known or potential PK interactions with SMV was manageable and resulted in few adjustments of concomitant medications. Our method could serve as a blueprint for the evaluation of the impact of DDIs.

Efficacy of a 12-Week Simeprevir Plus Peginterferon/Ribavirin (PR) Regimen in Treatment-Naïve Patients with Hepatitis C Virus (HCV) Genotype 4 (GT4) Infection and Mild-To-Moderate Fibrosis Displaying Early On-Treatment Virologic Response.

BACKGROUND: HCV GT4 accounts for up to 20% of HCV infections worldwide. Simeprevir, given for 12 weeks as part of a 24- or 48-week combination regimen with PR is approved for the treatment of chronic HCV GT4 infection. Primary study objectives were assessment of efficacy and safety of simeprevir plus PR in treatment-naïve patients with HCV GT4 treated for 12 weeks. Primary efficacy outcome was sustained virologic response 12 weeks post-treatment (SVR12). Additional objectives included investigation of potential associations of rapid virologic response and baseline factors with SVR12. METHODS: This multicentre, open-label, single-arm study (NCT01846832) evaluated efficacy and safety of simeprevir plus PR in 67 patients with HCV GT4 infection. Patients were treatment-naïve, aged 18-70 years with METAVIR F0-F2 fibrosis. Patients with early virologic response (HCV RNA <25 IU/mL [detectable/undetectable in IL28B CC patients or undetectable in IL28B CT/TT patients] at Week 2 and undetectable at Weeks 4 and 8) were eligible to stop all treatment at the end of Week 12, otherwise PR therapy was continued to Week 24. RESULTS: Of 67 patients treated, 34 (51%) qualified for 12-week treatment including all but one patient with IL28B CC genotype (14/15). All patients in the 12-week group had undetectable HCV RNA at end of treatment, and 97% (33/34) achieved SVR12. No new safety signals with simeprevir plus PR were identified. The proportion of patients experiencing Grade 3-4 adverse events was lower in the 12-week group than in the 24-week group. CONCLUSIONS: Our findings on simeprevir plus PR therapy shortened to 12 weeks in patients with HCV GT4 infection with favourable baseline characteristics and displaying early on-treatment virologic response are encouraging. No new safety signals were associated with simeprevir plus PR in this study. TRIAL REGISTRATION: NCT01846832.

Analysis of neurocognitive function and CNS endpoints in the PROTEA trial: darunavir/ritonavir with or without nucleoside analogues.

INTRODUCTION: During treatment with protease inhibitor monotherapy, the number of antiretrovirals with therapeutic concentrations in the cerebrospinal fluid (CSF) is lower, compared to standard triple therapy. However, the clinical consequences are unclear. METHODS: A total of 273 patients with HIV RNA <50 copies/mL for over 24 weeks on current antiretrovirals randomized to darunavir/ritonavir (DRV/r) 800/100 mg once-daily, either as monotherapy (n=137) or with 2NRTIs (n=136). Neurocognitive function was evaluated in all patients by the Hopkins Verbal Learning Tests, the Colour Trail Tests and the Grooved Pegboard Test at screening, baseline and at Week 48. A global neurocognitive score (NPZ-5) was derived by averaging the standardized results of the five domains. In a central nervous system (CNS) sub-study (n=70), HIV RNA levels in the CNS were evaluated at baseline and Week 48. Clinical adverse events related to the CNS were collected at each visit. RESULTS: Patients were 83% male and 88% White, with median age 43 years. There were more patients with nadir CD4 count below 200 cells/µL in the DRV/r monotherapy arm (41/137, 30%) than the triple therapy arm (30/136, 22%). At Week 48, there was no difference between the treatment arms for the five combined domains of the neurocognitive score. At Week 48, the percentage of patients with an abnormal neurocognitive score among the five domains was 12.2% for DRV/r monotherapy and 14.9% for triple therapy. However, one patient on DRV/r monotherapy with a CD4 nadir of 17 cells/µL was hospitalized with HIV encephalomyelitis at Week 24, with HIV RNA 2500 copies/mL in the CSF and 125 copies/mL in the plasma. Symptoms resolved after intensification with high dose zidovudine. A second patient on DRV/r monotherapy with CD4 nadir of 166 cells/µL had a rise in HIV RNA in CSF from <40 copies/mL at baseline to 654 copies/mL at Week 48, with concurrent plasma HIV RNA of 77 copies/mL. CONCLUSIONS: In this study for patients with HIV RNA <50 copies/mL at baseline, there was no difference in neurocognitive function between the treatment arms. However two patients on PI monotherapy with CD4 nadir <200 cells/µL developed viraemia in both CSF and plasma, with one symptomatic case. DRV/r monotherapy should be used with caution in patients with nadir CD4 counts below 200 cells/µL.

Safety, Reactogenicity, and Immunogenicity of Human Rotavirus Vaccine RIX4414 in Human Immunodeficiency Virus-positive Infants in South Africa.

BACKGROUND: rotavirus and human immunodeficiency virus (HIV) infections are a cause of great public health concern in developing countries. The current study evaluated the safety, reactogenicity, and immunogenicity of RIX4414 vaccine in asymptomatic or mildly symptomatic (clinical stages I and II according to WHO classification) HIV-infected South African infants. METHODS: a total of 100 HIV-positive infants aged 6 to 10 weeks enrolled in this double-blind, 1:1 randomized, placebo-controlled study were allocated into 2 groups to receive 3 doses of RIX4414 vaccine/placebo according to a 0-, 1-, and 2-month schedule. Routine vaccines were concomitantly administered. Solicited and unsolicited symptoms were recorded for 15 and 31 days after each dose, respectively. Serious adverse events were recorded throughout the study period. Serum antirotavirus IgA concentrations (enzyme-linked immunosorbent assay, cut-off ≥ 20 U/mL) and the immunodeficiency status were determined at screening and 2 months post-Dose 3. Stool samples were analyzed for rotavirus using enzyme-linked immunosorbent assay at predetermined points and during diarrhea episodes. RESULTS: all symptoms (solicited and unsolicited) occurred at a similar frequency in both groups. Six fatal serious adverse events in RIX4414 and 9 in placebo groups were reported. At 2 months post-Dose 3, the seroconversion rates were 57.1% (95% CI: 34-78.2) in RIX4414 and 18.2% (95% CI: 5.2-40.3) in the placebo group. The mean absolute CD4 cell count, CD4 percentage, and HIV-1 viral load were comparable in both groups at screening and 2 months post-Dose 3. Rotavirus shedding peaked at Day 7 after Dose 1 of RIX4414 with prolonged shedding was observed in 1 infant only. CONCLUSIONS: : Three doses of RIX4414 vaccine was tolerated well by the South African HIV-positive infants. A satisfactory immune response was mounted without aggravating their immunologic or HIV condition.