Population pharmacokinetics of ravidasvir in adults with chronic hepatitis C virus infection and impact of antiretroviral treatment.

Ravidasvir (RDV) is a novel NS5A inhibitor that exhibits potent pan-genotypic inhibition of hepatitis C virus (HCV) replication. Sofosbuvir (SOF) plus RDV was demonstrated to be efficacious and safe in adults with active HCV infection, including those living with HIV (LWHIV), in the STORM-C-1 trial. We assessed the population pharmacokinetics (PK) of RDV in a sub-study nested within STORM-C-1 conducted in Thailand and Malaysia. SOF (400 mg) plus RDV (200 mg) was administered orally once daily for 12 weeks to adults with chronic HCV infection, but without cirrhosis and for 24 weeks to those with compensated cirrhosis. Intensive and sparse PK samples were collected at 4, 8, and 12 weeks after treatment initiation. Population PK parameters of RDV and the impact of covariates were evaluated using nonlinear mixed-effects modeling. Five hundred ninety-four participants were included, 235 (40%) had compensated cirrhosis, and 189 (32%) were LWHIV. RDV plasma concentrations were best described by a two-compartment model with first-order elimination. Oral clearance (CL/F) and volume of distribution (Vd/F) parameters were allometrically scaled on fat-free mass. Concomitant antiretroviral treatment (ART) increased RDV CL/F by 30%-60%, with efavirenz-based ART having the largest impact. Females had 16% lower RDV CL/F than males, and higher albumin levels reduced RDV central volume of distribution. While several covariates impact RDV CL/F and Vd/F, the effect on RDV exposures was not clinically relevant based on the efficacy data reported in this diverse Asian adult population. There were no meaningful drug-drug interactions in adults LWHIV on ART.

Population Pharmacokinetics of Pediatric Lopinavir/Ritonavir Oral Pellets in Children Living with HIV in Africa.

Antiretroviral therapy for children living with HIV (CLHIV) under 3 years of age commonly includes lopinavir/ritonavir (LPV/r). However, the original liquid LPV/r formulation has taste and cold storage difficulties. To address these challenges, LPV/r oral pellets have been developed. These pellets can be mixed with milk or food for administration and do not require refrigeration. We developed the population pharmacokinetic (PK) model and assessed drug exposure of LPV/r oral pellets administered twice daily to CLHIV per World Health Organization (WHO) weight bands. The PK analysis included Kenyan and Ugandan children participating in the LIVING studies (NCT02346487) receiving LPV/r pellets (40/10 mg) and ABC/3TC (60/30 mg) dispersible tablets. Population PK models were developed for lopinavir (LPV) and ritonavir (RTV) to evaluate the impact of RTV on the oral clearance (CL/F) of LPV. The data obtained from the study were analyzed using nonlinear mixed-effects modeling approach. Data from 514 children, comprising a total of 2,998 plasma concentrations of LPV/r were included in the analysis. The LPV and RTV concentrations were accurately represented by a one-compartment model with first-order absorption (incorporating a lag-time) and elimination. Body weight influenced LPV and RTV PK parameters. The impact of RTV concentrations on the CL/F of LPV was characterized using a maximum effect model. Simulation-predicted target LPV exposures were achieved in children with this pellet formulation across the WHO weight bands. The LPV/r pellets dosed in accordance with WHO weight bands provide adequate LPV exposures in Kenyan and Ugandan children weighing 3.0 to 24.9 kg.

Abacavir Drug Exposures in African Children Under 14 kg Using Pediatric Solid Fixed Dose Combinations According to World Health Organization Weight Bands.

BACKGROUND: The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing <14 kg and receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population pharmacokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands. METHODS: Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets (60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV. ABC exposures (AUC0-24) of 6.4-50.4 mg h/L were used as targets. RESULTS: Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F) and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of age). Exposures to ABC were within the target range for children weighing 6.0-24.9 kg, but children weighing 3-5.9 kg were predicted to be overexposed. CONCLUSIONS: Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3-5.9 kg increased the proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical implications and safety of the proposed alternative ABC doses.

Efficacy and safety of ravidasvir plus sofosbuvir in patients with chronic hepatitis C infection without cirrhosis or with compensated cirrhosis (STORM-C-1): interim analysis of a two-stage, open-label, multicentre, single arm, phase 2/3 trial.

BACKGROUND: In low-income and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, and sofosbuvir has shown efficacy and safety in patients with chronic HCV genotype 4 infection. STORM-C-1 trial aimed to assess the efficacy and safety of ravidasvir plus sofosbuvir in a diverse population of adults chronically infected with HCV. METHODS: STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-3) aged 18-69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA <12 IU/mL in Thailand and HCV RNA <15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183. FINDINGS: Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94-99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment. INTERPRETATION: In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality. FUNDING: National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.

Improving the accuracy of pulsed field gradient NMR diffusion experiments: Correction for gradient non-uniformity.

Pulsed field gradient NMR is a well-established technique for the determination of self-diffusion coefficients. However, a significant source of systematic error exists in the spatial variation of the applied pulsed field gradient. Non-uniform pulsed field gradients cause the decay of peak amplitudes to deviate from the expected exponential dependence on gradient squared. This has two undesirable effects: the apparent diffusion coefficient will deviate from the true value to an extent determined by the choice of experimental parameters, and the error estimated by the nonlinear least squares fitting will contain a significant systematic contribution. In particular, the apparent diffusion coefficient determined by exponential fitting of the diffusional attenuation of NMR signals will depend both on the exact pulse widths used and on the range of gradient amplitudes chosen. These problems can be partially compensated for if experimental attenuation data are fitted to a function corrected for the measured spatial dependence of the gradient and signal strength. This study describes a general alternative to existing methods for the calibration of NMR diffusion measurements. The dominant longitudinal variation of the pulsed field gradient amplitude and the signal strength are mapped by measuring pulsed field gradient echoes in the presence of a weak read gradient. These data are then used to construct a predicted signal decay function for the whole sample, which is parameterised as the exponential of a power series. Results are presented which compare diffusion coefficients obtained using the new calibration method with previous literature values.

Nuclear magnetic resonance investigation of the interaction of water vapor with sildenafil citrate in the solid state.

Solid-state carbon-13 (13C) and nitrogen-15 (15N) nuclear magnetic resonance (NMR) have been used to investigate how water interacts with sildenafil citrate. When the humidity is altered, the water concentration in the solid compound changes in a reversible manner. The proportion of occupied sites depends on the humidity, but the water concentration never reaches a rational (e.g., 1:1) stoichiometric ratio to form a true hydrate. The NMR spectra were obtained under several humidity-controlled conditions to determine what changes occur as the water content is varied and where the water is located in the crystal structure. Only one set of 15N and 13C signals is observed for each humidity level. This shows that water incorporated into the crystal lattice of sildenafil citrate is very mobile and exchanges rapidly on the NMR time scale between various sites. The 13C data are consistent with formation of a hydrogen bond between a water molecule and one carbonyl of the citrate anion. The spectra also show that the water content affects the environment (perhaps influencing the average conformation) of the propyl group. Additionally, 15N dipolar dephasing experiments show that the sildenafil molecule is only protonated in the piperazine ring. The work is supported by solution-state NMR.