Model-based meta-analysis to quantify the effects of short interfering RNA therapeutics on hepatitis B surface antigen turnover in hepatitis B-infected mice.

The objective of this study was to compare the efficacy of short interfering RNA therapeutics (siRNAs) in reducing hepatitis B surface antigen (HBsAg) levels in hepatitis B-infected (HBV) mice across multiple siRNA therapeutic classes using model-based meta-analysis (MBMA) techniques. Literature data from 10 studies in HBV-infected mice were pooled, including 13 siRNAs, formulated as liposomal nanoparticles (LNPs) or conjugated to either cholesterol (chol) or N-acetylgalactosamine (GalNAc). Time course of the baseline- and placebo-corrected mean HBsAg profiles were modeled using kinetics of drug effect (KPD) model coupled to an indirect response model (IRM) within a longitudinal non-linear mixed-effects MBMA framework. Single and multiple dose simulations were performed exploring the role of dosing regimens across evaluated siRNA classes. The HBsAg degradation rate (0.72 day-1) was consistent across siRNAs but exhibited a large between-study variability of 31.4% (CV%). The siRNA biophase half-life was dependent on the siRNA class and was highest for GalNAc-siRNAs (21.06 days) and lowest for chol-siRNAs (2.89 days). ID50 estimates were compound-specific and were lowest for chol-siRNAs and highest for GalNAc-siRNAs. Multiple dose simulations suggest GalNAc-siRNAs may require between 4 and 7 times less frequent dosing at higher absolute dose levels compared to LNP-siRNAs and chol-siRNAs, respectively, to reach equipotent HBsAg-lowering effects in HBV mice. In conclusion, non-clinical HBsAg concentration-time data after siRNA administration can be described using the presented KPD-IRM MBMA framework. This framework allows to quantitatively compare the effects of siRNAs on the HBsAg time course and inform dose and regimen selection across siRNA classes. These results may support siRNA development, optimize preclinical study designs, and inform data analysis methodology of future anti-HBV siRNAs; and ultimately, support siRNA model-informed drug development (MIDD) strategies.

Population pharmacokinetics of lisinopril in hypertensive children and adolescents with normal to mildly reduced kidney function.

AIMS: Lisinopril, an angiotensin-converting enzyme inhibitor, is a frequently prescribed antihypertensive drug in the paediatric population, while being used off-label under the age of 6 years in the USA and for all paediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive paediatric patients corresponding with the day-to-day clinical population. METHODS: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05 to 0.2 mg kg-1 . Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2 kg (median 53.2 kg). All data were analysed using Monolix version 2020R1 (Lixoft, France) and R version 3.6.2. RESULTS: A 1-compartment model with first-order absorption and first-order elimination optimally describes the data. Parameter estimates of absorption rate constant (0.075 h-1 [0.062, 0.088], typical value [95% confidence interval]), volume of distribution (31.38 L 70 kg-1 [10.5, 52.3]) and elimination clearance (24.2 L h-1 70 kg-1 [19.5, 28.9]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a linear effect centred around 105 mL min-1  1.73 m-2 . The effects of body weight were implemented using fixed allometric exponents centred around an adult weight of 70 kg. CONCLUSION: Lisinopril dose and regimen adjustments for paediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen.

The Use of Population Pharmacokinetics to Extrapolate Food Effects from Human Adults and Beagle Dogs to the Pediatric Population Illustrated with Paracetamol as a Test Case.

To date, food-drug interactions in the pediatric population remain understudied. The current food effect studies are mostly performed in adults and do not mimic the real-life situation in the pediatric population. Since the potential benefits of food effect studies performed in pediatrics should be counterbalanced with the burden that these studies pose to the patients, alternative research strategies should be evaluated. The present study aimed to evaluate whether population pharmacokinetics (popPK) using data in beagle dogs and human adults could reliably assess food effects relevant for the pediatric population. PopPK was utilized to understand the performance of paracetamol under different dosing conditions (when the participants were fasted, with a reference meal, and with infant formula) in human adults (n = 8) and beagle dogs (n = 6) by constructing models to derive the pharmacokinetic parameters and to evaluate the food effects in both species. A two-compartment model with a single input function for the absorption phase best described the profiles of paracetamol in the beagle dogs. In the human adults, a one-compartment model with a dual input function for the absorption phase best described the data. The simulated profiles for the different dosing conditions demonstrated that both the human adults' and beagle dogs' simulations were able to acceptably describe the plasma concentration-time profiles of paracetamol observed in a representative pediatric population, which opens up perspectives on pediatric-relevant food effect predictions. However, the obtained results should be carefully interpreted, since an accurate validation of these findings was not possible due to the scarcity of the literature on observed pediatric data.

Plasma and Liver Pharmacokinetics of the N-Acetylgalactosamine Short Interfering RNA JNJ-73763989 in Recombinant Adeno-Associated-Hepatitis B Virus-Infected Mice.

JNJ-73763989 is an N-acetylgalactosamine conjugated short interfering RNA combination product consisting of two triggers in clinical development for chronic hepatitis B virus (HBV) infection treatment that induces a selective degradation of all HBV mRNA transcripts. Our aim is to characterize the plasma and liver pharmacokinetics (PK) of JNJ-73763989 after intravenous and subcutaneous administration in recombinant adeno-associated (rAAV) HBV infected mice. Forty-two male rAAV-HBV infected C57Bl/6 mice received JNJ-73763989 doses of 10 mg/kg i.v. or 1, 3 and 10 mg/kg s.c. Plasma and liver concentrations were analyzed simultaneously using nonlinear mixed-effects modeling with the NONMEM 7.4. A population PK model consisting of a two-compartment disposition model with transporter-mediated drug disposition, including internalization to the liver compartment, linear elimination from plasma and liver, and first-order absorption following subcutaneous administration, was suitable to describe both plasma and liver PK. After subcutaneous dosing, absolute bioavailability was complete and flip-flop kinetics were observed. JNJ-73763989 distributes from plasma to liver via transporter-mediated liver internalization in less than 24 hours, with sustained (>42 days) liver exposure. The saturation of transporter-mediated liver internalization was hypothesized to be due to asialoglycoprotein receptor saturation. Increasing the dose decreased the relative liver uptake efficiency in mice for intravenously and, to a lesser extent, subcutaneously administered JNJ-73763989. Lower dose levels administered subcutaneously in mice can maximize the proportion of the dose reaching the liver. SIGNIFICANCE STATEMENT: Pharmacokinetic modeling of JNJ-73763989 liver and plasma concentration-time data in mice indicated that the proportion of JNJ-73763989 reaching the liver may be increased by administering lower subcutaneous doses compared to higher intravenous doses. Model-based simulations can be applied to optimize the dose and regimen combination.

Phase I study of intraperitoneal aerosolized nanoparticle albumin based paclitaxel (NAB-PTX) for unresectable peritoneal metastases.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel method to treat patients with peritoneal metastases (PM). We aimed to study the tolerability, safety, pharmacokinetics, and tumour response of nanoparticle albumin bound paclitaxel (NAB-PTX) during PIPAC in a Phase I study. METHODS: Eligible patients with biopsy-proven PM from ovarian, breast, gastric, hepatobiliary, or pancreatic origin underwent three PIPAC treatments using NAB-PTX with a four-week interval. The dose of NAB-PTX was escalated from 35 to 140 mg/m2 using a Bayesian design to estimate the maximum tolerated dose (MTD). FINDINGS: Twenty-three patients were included; thirteen (65%) patients combined PIPAC therapy with continued systemic chemotherapy. The most frequent toxicities were liver toxicity and anaemia. Treatment resulted in seven (35%) responders, six (30%) non-responders and seven (35%) patients with stable PM. Systemic absorption of NAB-PTX was slow, with median peak plasma concentrations reached after 3 to 4 h. Median NAB-PTX tumour tissue concentrations suggested accumulation: 14.6 ng/mg, 19.2 ng/mg and 40.8 ng/mg after the first, second and third PIPAC procedure respectively. EORTC QoL and VAS scores remained stable. Overall survival after one year was 57%. INTERPRETATION: PIPAC with NAB-PTX results in a favourable PK profile and promising anticancer activity in patients with unresectable PM. The MTD and recommended Phase II clinical trial dose are 140 mg/m2. In patients with impaired hepatobiliary function, a dose of 112.5 mg/m2 is recommended. FUNDING: Kom op tegen Kanker (Flemish League against Cancer).

Population pharmacokinetics of propofol in neonates and infants: Gestational and postnatal age to determine clearance maturation.

AIMS: Develop a population pharmacokinetic model describing propofol pharmacokinetics in (pre)term neonates and infants, that can be used for precision dosing (e.g. during target-controlled infusion) of propofol in this population. METHODS: A nonlinear mixed effects pharmacokinetic analysis (Monolix 2018R2) was performed, based on a pooled study population in 107 (pre)term neonates and infants. RESULTS: In total, 836 blood samples were collected from 66 (pre)term neonates and 41 infants originating from 3 studies. Body weight (BW) of the pooled study population was 3.050 (0.580-11.440) kg, postmenstrual age (PMA) was 36.56 (27.00-43.00) weeks and postnatal age (PNA) was 1.14 (0-104.00) weeks (median and min-max range). A 3-compartment structural model was identified and the effect of BW was modelled using fixed allometric exponents. Elimination clearance maturation was modelled accounting for the maturational effect on elimination clearance until birth (by gestational age [GA]) and postpartum (by PNA and GA). The extrapolated adult (70 kg) population propofol elimination clearance (1.64 L min-1 , estimated relative standard error = 6.02%) is in line with estimates from previous population pharmacokinetic studies. Empirical scaling of BW on the central distribution volume in function of PNA improved the model fit. CONCLUSIONS: It is recommended to describe elimination clearance maturation by GA and PNA instead of PMA on top of size effects when analyzing propofol pharmacokinetics in populations including preterm neonates. Changes in body composition in addition to weight changes or other physio-anatomical changes may explain the changes in central distribution volume. The developed model may serve as a prior for propofol dose finding and target-controlled infusion in (preterm) neonates.

High-dose etoposide formulations do not saturate intestinal P-glycoprotein: Development, stability, and pharmacokinetics in Sprague-Dawley rats.

It has been suggested that oral absorption of low-permeable P-glycoprotein (P-gp) substrates can be increased through saturation of P-gp. For BCS class IV drug substances, saturating P-gp is challenging due to low aqueous solubility. The present study investigated if the BCS IV drug substance etoposide could be solubilized to a concentration saturating P-gp after oral administration. A formulation consisting of 10% (w/v) of pluronic® F-127 and polyvinylpyrrolidone/vinyl acetate (PVP/VA), and 57% (v/v) ethanol enhanced etoposide's solubility approximately 100 times (16 mg mL-1) compared to its aqueous solubility. In vitro, this formulation was stable upon dilution in simulated intestinal fluid. In male Sprague-Dawley rats, oral administration of increasing solubilized etoposide doses using the formulation matrix increased the AUC0-∞ of etoposide dose-proportionally but resulted in a lower absolute oral bioavailability (F) and rate of absorption as compared to control. At the highest investigated dose (100 mg kg-1), AUC0-∞ and Cmax were significantly increased by 2.9- and 1.4-fold, respectively, compared to control dosed at 20 mg kg-1. A single oral dose of 20 mg kg-1 zosuquidar followed by 20 mg kg-1 oral etoposide increased F 8.6-fold. In conclusion, a stable formulation with improved etoposide solubility was developed, yet the formulation did not result in increased oral bioavailability of etoposide.