Population pharmacokinetics of the dual endothelin receptor antagonist aprocitentan in subjects with or without essential or resistant hypertension.

Aprocitentan is a novel, potent, dual endothelin receptor antagonist that recently demonstrated efficacy in the treatment of difficult-to-treat (resistant) hypertension. The aim of this study was to develop a population pharmacokinetic (PK) model describing aprocitentan plasma concentration over time, to investigate relationships between subject-specific factors (covariates) and model parameters, and to quantify the influence of the identified covariates on the exposure to aprocitentan via model-based simulations, enabling judgment about the clinical relevance of the covariates.PK data from 902 subjects in ten Phase 1, one Phase 2, and one Phase 3 study were pooled to develop a joint population PK model. The concentration-time course of aprocitentan was described by a two-compartment model with absorption lag time, first-order absorption and elimination, and reduced relative bioavailability following very high doses of 300 and 600 mg.The population PK model described the observed data well. Volume and clearance parameters were associated with body weight. Renal function as reflected by estimated glomerular filtration rate (eGFR), hepatic impairment, and sex were identified as relevant covariates on clearance.The subject-specific characteristics of body weight, eGFR, hepatic impairment, and sex were shown to influence exposure parameters area under the concentration-time curve and maximum concentration in steady state to a limited extent, i.e., not more than 25% different from a reference subject, and therefore do not warrant dose adjustments.

Population pharmacokinetic modeling of daridorexant, a novel dual orexin receptor antagonist.

The analysis aimed at identifying subject-specific characteristics (covariates) influencing exposure to daridorexant and quantification of covariate effects to determine clinical relevance. Data from 13 phase I, two phase II, and two phase III studies were pooled to develop a population pharmacokinetic model describing daridorexant concentration over time. Covariate effects were quantified based on model predictions. A two-compartment model with dose-dependent bioavailability, absorption lag time, linear absorption, and nonlinear elimination described the data best. Statistically significant covariates were food status on absorption (lag time and rate constant), time of drug administration (morning, bedtime) on absorption rate constant, lean body weight on central volume of distribution and elimination, fat mass on peripheral volume of distribution and intercompartmental drug transfer, and age and alkaline phosphatase on elimination. Age, lean body weight, fat mass, and alkaline phosphatase influence exposure (area under the curve, time of maximum concentration after dose administration, maximum plasma concentration, and next-morning concentration) to a limited extent, that is, less than 20% difference from a typical subject. Morning administration is not relevant for daridorexant use by insomnia patients. The food effect with simultaneous intake of a high-fat, high-calorie food is an extreme-case scenario unlikely to occur in clinical practice. Body composition, alkaline phosphatase, and age showed clinically negligible effects on exposure to daridorexant. Lean body weight and fat mass described the pharmacokinetics of daridorexant better than other body size descriptors (body weight, height, body mass index), suggesting a convenient physiological alternative to reduce the number of covariates in population pharmacokinetic models. The results indicate that differences between subjects do not require dose adjustments.

Pharmacokinetic modelling and simulation to optimize albendazole dosing in hookworm- or Trichuris trichiura-infected infants to adults.

BACKGROUND: Albendazole is the most commonly used drug in preventive chemotherapy programmes against soil-transmitted helminth (STH) infections, with the standard dose of 400 mg resulting in suboptimal clinical outcomes. Population pharmacokinetic (PK) models that could inform dosing strategies are not yet available. METHODS: A population pharmacokinetic model was developed based on micro-blood samples collected from 252 patients aged 2 to 65 years, infected with either hookworm or Trichuris trichiura and treated with albendazole doses ranging from of 200 to 800 mg. An exposure-response analysis was performed relating albendazole and its two metabolites to cure rates and egg reduction rates (ERR). Finally, model-based simulations were conducted to determine equivalent exposure coverage in infants to adults. RESULTS: A population PK model, with one distribution compartment for each compound and one peripheral compartment, following oral administration with a lag time, assuming first-order absorption and linear elimination, best described the concentration-time profiles. Clearance and volume parameters were scaled to body size (weight for albendazole and height for albendazole sulfoxide and sulfone). Dose proportionality was observed for the active metabolite, albendazole sulfoxide, but only in hookworm-infected individuals, with increasing exposure resulting in increased ERR. Exposure of sulfoxide was lowest in the tallest individuals. CONCLUSIONS: Pharmacometric simulations indicate that doses up to 800 mg could further increase albendazole efficacy in hookworm-infected adults, whereas the standard dose of 400 mg is sufficient in the youngest age cohorts. In the absence of evidence-based arguments for adjusting albendazole doses in T. trichiura-infected individuals, the search for new treatment options is further emphasized.

Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans.

Antagonism of the chemokine receptor CXCR7 has shown promising effects in diverse disease areas through modulation of its ligands, CXCL11 and CXCL12. Preclinical data of the first-in-class CXCR7 antagonist, ACT-1004-1239, showed efficacy in animal models of multiple sclerosis and acute lung injury. In healthy humans, single-dose administration of ACT-1004-1239 revealed a favorable clinical profile. Here, we report the target engagement of ACT-1004-1239 in healthy mice and humans after multiple doses using CXCL11 and CXCL12 as biomarkers. In addition, safety/tolerability, concentration-QTc relationship, and pharmacokinetics (PK) were assessed in a randomized, double-blind, placebo-controlled Phase 1 clinical study. Multiple-dose ACT-1004-1239 dose-dependently increased CXCL12 plasma concentration across the investigated dose range in mice and humans (mice: 1-100 mg/kg b.i.d.; humans: 30-200 mg o.d.) when compared to vehicle/placebo demonstrating target engagement. Mouse and human PK/PD models predicted that CXCL12 concentration approached a plateau within these dose ranges. In humans, ACT-1004-1239 was rapidly absorbed (tmax: 1.75-3.01 h) and the terminal t1/2 was approximately 19 h. Steady-state conditions were reached by Day 3 with an accumulation index of 1.2. Female subjects had overall higher exposure compared to males. Multiple-dose ACT-1004-1239 was well tolerated up to 200 mg once daily in humans. There was no evidence of ACT-1004-1239-mediated QTc interval prolongation. Overall, multiple oral doses of ACT-1004-1239 showed target engagement with CXCR7 in healthy mice and humans, therefore, assessment of CXCL12 as translational tool for further investigations in patients is warranted. Favorable safety/tolerability and PK profiles allow for further clinical development.

Insufficient Stability of Clavulanic Acid in Widely Used Child-Appropriate Formulations.

Amoxicillin-clavulanic acid (AMC) belongs to the WHO Essential Medicines List for children, but for optimal antimicrobial effectiveness, reconstituted dry powder suspensions need to be stored in a refrigerated environment. Many patients in low- and middle-income countries who are sold AMC suspensions would be expected not to keep to the specified storage conditions. We aimed to assess the stability of both ingredients in liquid formulations and dispersible tablets, combined with nationally representative data on access to appropriate storage. Degradation of amoxicillin (AMX) and clavulanic-acid (CLA) was measured in suspensions and dispersible tablets commercially available in Switzerland at different ambient temperatures (8 °C vs. 28 °C over 7 days, and 23 °C vs. 28 °C over 24 h, respectively). Data on access to refrigeration and electricity were assessed from the USAID-funded Demographic and Health Survey program. In suspensions, CLA degraded to a maximum of 12.9% (95% CI -55.7%, +29.9%) at 8°C and 72.3% (95% CI -82.8%, -61.8%) at a 28 °C ambient temperature during an observation period of 7 days. Dispersible tablets were observed during 24 h and CLA degraded to 15.4% (95% CI -51.9%, +21.2%) at 23 °C and 21.7% (-28.2%, -15.1%) at a 28 °C ambient temperature. There is relevant degradation of CLA in suspensions during a 7-day course. To overcome the stability challenges for all active components, durable child-appropriate formulations are needed. Until then, prescribers of AMC suspensions or pharmacists who sell the drug need to create awareness for the importance of proper storage conditions regarding effectiveness of both antibiotics and this recommendation should be reflected in the WHO Essential Medicines List for children.

Pharmacometric Analysis of Tribendimidine Monotherapy and Combination Therapies To Achieve High Cure Rates in Patients with Hookworm Infections.

In the treatment of hookworm infections, pharmacotherapy has been only moderately successful and drug resistance is a threat. Therefore, novel treatment options including combination therapies should be considered, in which tribendimidine could play a role. Our aims were to (i) characterize the pharmacokinetics of tribendimidine's metabolites in adolescents receiving tribendimidine monotherapy or in combination with ivermectin or oxantel pamoate, (ii) evaluate possible drug-drug interactions (DDI), (iii) link exposure to response, and (iv) identify a treatment strategy associated with high efficacy, i.e., >90% cure rates (CRs), utilizing model-based simulations. A population pharmacokinetic model was developed for tribendimidine's primary and secondary metabolites, dADT and adADT, in 54 hookworm-positive adolescents, with combination therapy evaluated as a possible covariate. Subsequently, an exposure-response analysis was performed utilizing CRs as response markers. Simulations were performed to identify a treatment strategy to achieve >90% CRs. A two-compartmental model best described metabolite disposition. No pharmacokinetic DDI was identified with ivermectin or oxantel pamoate. All participants receiving tribendimidine plus ivermectin were cured. For the monotherapy arm and the arm including the combination with oxantel pamoate, Emax models adequately described the correlation between dADT exposure and probability of being cured, with required exposures to achieve 50% of maximum effect of 39.6 and 15.6 nmol/ml·h, respectively. Based on our simulations, an unrealistically high monotherapy tribendimidine dose would be necessary to achieve CRs of >90%, while combination therapy with ivermectin would meet this desired target product profile. Further clinical studies should be launched to develop this combination for the treatment of hookworm and other helminth infections.

Population Pharmacokinetics and Exposure-Response Analysis of Tribendimidine To Improve Treatment for Children with Hookworm Infection.

Tribendimidine has been successful in treating hookworm infections and may serve as an alternative to albendazole should resistance arise. Our aims were to (i) characterize the pharmacokinetics (PK) of tribendimidine's primary metabolite, deacetylated amidantel (dADT), and secondary metabolite, acetylated derivative of amidantel (adADT), in school-aged children and adolescents, (ii) link exposure to efficacy against hookworm, and (iii) evaluate whether tribendimidine pharmacotherapy in children could be further improved. First, a population PK model was developed based on dried-blood-spot samples collected from 155 school-aged children and adolescents with hookworm infections, following tribendimidine doses ranging from 100 to 400 mg. Second, an exposure-response analysis was conducted to link the active metabolite dADT to cure rates (CRs) and egg reduction rates (ERRs). Third, simulations were performed to identify a treatment strategy associated with >90% CRs. A two-compartmental model with transit compartments describing observed delay in absorption adequately described PK data of dADT and adADT. Allometric scaling was included to account for growth and development. The absorption rate was 56% lower with 200-mg tablets than with 50-mg tablets, while the extent of absorption remained unaffected. The identified Emax models linking dADT exposure to ERRs and CRs showed shallow curves, as increasing exposure led to marginal efficacy increase. Combination therapy should be considered, as a 12-fold-higher dose would be needed to achieve 95% ERRs and CRs >90% with tribendimidine alone. Further studies are warranted to evaluate safety of higher tribendimidine doses and combination therapies with other anthelmintic agents to improve treatment strategy for children with hookworm infection.

A Pediatric Covariate Function for CYP3A-Mediated Midazolam Clearance Can Scale Clearance of Selected CYP3A Substrates in Children.

Recently a framework was presented to assess whether pediatric covariate models for clearance can be extrapolated between drugs sharing elimination pathways, based on extraction ratio, protein binding, and other drug properties. Here we evaluate when a pediatric covariate function for midazolam clearance can be used to scale clearance of other CYP3A substrates. A population PK model including a covariate function for clearance was developed for midazolam in children aged 1-17 years. Commonly used CYP3A substrates were selected and using the framework, it was assessed whether the midazolam covariate function accurately scales their clearance. For eight substrates, reported pediatric clearance values were compared numerically and graphically with clearance values scaled using the midazolam covariate function. For sildenafil, clearance values obtained with population PK modeling based on pediatric concentration-time data were compared with those scaled with the midazolam covariate function. According to the framework, a midazolam covariate function will lead to systemically accurate clearance scaling (absolute prediction error (PE) < 30%) for CYP3A substrates binding to albumin with an extraction ratio between 0.35 and 0.65 when binding < 10% in adults, between 0.05 and 0.55 when binding > 90%, and with an extraction ratio ranging between these values when binding between 10 and 90%. Scaled clearance values for eight commonly used CYP3A substrates were reasonably accurate (PE < 50%). Scaling of sildenafil clearance was accurate (PE < 30%). We defined for which CYP3A substrates a pediatric covariate function for midazolam clearance can accurately scale plasma clearance in children. This scaling approach may be useful for CYP3A substrates with scarce or no available pediatric PK information.

Ivermectin Dosing Strategy to Achieve Equivalent Exposure Coverage in Children and Adults.

Ivermectin is a commonly used broad-spectrum antiparasitic drug, yet doses that produce consistent exposure coverage across age have not been characterized, and no data are available in children weighing < 15 kg. First, a population pharmacokinetic model is developed based on data from 200 children and 11 adults, treated with 100-600 µg/kg ivermectin. Second, model-based simulations are performed to identify a dosing strategy that achieves equivalent exposure coverage in children and adults. Median (90% confidence interval) clearance of 0.346 (0.12-0.73) L/hour/kg in pre-school-aged (2-5 years) children is similar to 0.352 (0.17-0.69) L/hour/kg in school-aged (6-12 years) children but higher than in adults (0.199 (0.10-0.31) L/hour/kg), resulting in significantly lower exposure in children following a 200 µg/kg dose. Simulations indicate that a dose increase to 300 and 250 µg/kg in children aged 2-5 and 6-12 years, respectively, will achieve equivalent ivermectin exposure coverage in children and adults.

Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach.

PURPOSE: Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates. METHODS: Pharmacokinetic (PK) data of midazolam and 1-OH-midazolam from 264 post-operative children 1-18 years of age after oral administration were analyzed using a physiological population PK modelling approach. In the model, consisting of physiological compartments representing the gastro-intestinal tract and liver,intrinsic intestinal and hepatic clearances were estimated to derive values for bioavailability and plasma clearance. RESULTS: The whole-organ intrinsic clearance in the gut wall and liver were found to increase with body weight, with a 105 (95% confidence interval (CI): 5-405) times lower intrinsic gut wall clearance than the intrinsic hepatic clearance (i.e. 5.08 L/h (relative standard error (RSE) 10%) versus 527 L/h (RSE 7%) for a 16 kg individual, respectively). When expressed per gram of organ, intrinsic clearance increases with increasing body weight in the gut wall, but decreases in the liver, indicating that CYP3A-mediated intrinsic clearance and local bioavailability in the gut wall and liver do not change with age in parallel. The resulting total bioavailability was found to be age-independent with a median of 20.8% in children (95%CI: 3.8-50.0%). CONCLUSION: In conclusion, the intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance in children from 1 to 18 years of age, and contributes less to the overall first-pass metabolism compared to adults.

First-Pass CYP3A-Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates.

To predict first-pass and systemic cytochrome P450 (CYP) 3A-mediated metabolism of midazolam in preterm neonates, a physiological population pharmacokinetic model was developed describing intestinal and hepatic midazolam clearance in preterm infants. On the basis of midazolam and 1-OH-midazolam concentrations from 37 preterm neonates (gestational age 26-34 weeks) receiving midazolam orally and/or via a 30-minute intravenous infusion, intrinsic clearance in the gut wall and liver were found to be very low, with lower values in the gut wall (0.0196 and 6.7 L/h, respectively). This results in a highly variable and high total oral bioavailability of 92.1% (range, 67-95%) in preterm neonates, whereas this is around 30% in adults. This approach in which intestinal and hepatic clearance were separately estimated shows that the high bioavailability in preterm neonates is explained by, likely age-related, low CYP3A activity in the liver and even lower CYP3A activity in the gut wall.

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure.

AIMS: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice. METHODS: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l-1 and 0-4 failing organs) using graphical and numerical diagnostics. RESULTS: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) <30%]. Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%). CONCLUSION: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates.

Children in clinical trials: towards evidence-based pediatric pharmacotherapy using pharmacokinetic-pharmacodynamic modeling.

INTRODUCTION: In pediatric pharmacotherapy, many drugs are still used off-label, and their efficacy and safety is not well characterized. Different efficacy and safety profiles in children of varying ages may be anticipated, due to developmental changes occurring across pediatric life. AREAS COVERED: Beside pharmacokinetic (PK) studies, pharmacodynamic (PD) studies are urgently needed. Validated PKPD models can be used to derive optimal dosing regimens for children of different ages, which can be evaluated in a prospective study before implementation in clinical practice. Strategies should be developed to ensure that formularies update their drug dosing guidelines regularly according to the most recent advances in research, allowing for clinicians to integrate these guidelines in daily practice. Expert commentary: We anticipate a trend towards a systems-level approach in pediatric modeling to optimally use the information gained in pediatric trials. For this approach, properly designed clinical PKPD studies will remain the backbone of pediatric research.

Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children.

RATIONALE: Various in vitro, animal, and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on cytochrome P-450 3A (CYP3A)-mediated drug metabolism. Studies showing this relationship in critically ill patients are lacking, whereas clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity. OBJECTIVES: To prospectively study the relationship between inflammation, organ failure, and midazolam clearance as a validated marker of CYP3A-mediated drug metabolism in critically ill children. METHODS: From 83 critically ill children (median age, 5.1 mo [range, 0.02-202 mo]), midazolam plasma (n = 532), cytokine (e.g., IL-6, tumor necrosis factor-α), and C-reactive protein (CRP) levels; organ dysfunction scores (Pediatric Risk of Mortality II, Pediatric Index of Mortality 2, Pediatric Logistic Organ Dysfunction); and number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3. MEASUREMENTS AND MAIN RESULTS: In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. CRP and organ failure were significantly associated with clearance (P < 0.01), explaining both interindividual and interoccasional variability. In simulations, a CRP of 300 mg/L was associated with a 65% lower clearance compared with 10 mg/L, and three failing organs were associated with a 35% lower clearance compared with one failing organ. CONCLUSIONS: Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity.

Pharmacokinetic-Pharmacodynamic Model for the Effect of l-Arginine on Endothelial Function in Patients with Moderately Severe Falciparum Malaria.

Impaired organ perfusion in severe falciparum malaria arises from microvascular sequestration of parasitized cells and endothelial dysfunction. Endothelial dysfunction in malaria is secondary to impaired nitric oxide (NO) bioavailability, in part due to decreased plasma concentrations of l-arginine, the substrate for endothelial cell NO synthase. We quantified the time course of the effects of adjunctive l-arginine treatment on endothelial function in 73 patients with moderately severe falciparum malaria derived from previous studies. Three groups of 10 different patients received 3 g, 6 g, or 12 g of l-arginine as a half-hour infusion. The remaining 43 received saline placebo. A pharmacokinetic-pharmacodynamic (PKPD) model was developed to describe the time course of changes in exhaled NO concentrations and reactive hyperemia-peripheral arterial tonometry (RH-PAT) index values describing endothelial function and then used to explore optimal dosing regimens for l-arginine. A PK model describing arginine concentrations in patients with moderately severe malaria was extended with two pharmacodynamic biomeasures, the intermediary biochemical step (NO production) and endothelial function (RH-PAT index). A linear model described the relationship between arginine concentrations and exhaled NO. NO concentrations were linearly related to RH-PAT index. Simulations of dosing schedules using this PKPD model predicted that the time within therapeutic range would increase with increasing arginine dose. However, simulations demonstrated that regimens of continuous infusion over longer periods would prolong the time within the therapeutic range even more. The optimal dosing regimen for l-arginine is likely to be administration schedule dependent. Further studies are necessary to characterize the effects of such continuous infusions of l-arginine on NO and microvascular reactivity in severe malaria.

Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration.

PURPOSE: Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs, the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults. METHODS: In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1,760 patients (age 1 day-18 years, bodyweight 415 g-85 kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR, one GFR maturational function was derived for all three drugs. RESULTS: Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight-dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (ClGFR = Cldrug*(BW/4 kg)(BDE) with BDE = 2.23*BW(-0.065)). Population clearance values (Cldrug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, respectively. DISCUSSION: Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children.