Model-based assessment of the safety of community interventions with primaquine in sub-Saharan Africa

Background Single low-dose primaquine (SLD-PQ) is recommended in combination with artemisinin-based combination therapy to reduce Plasmodium falciparum transmission in areas threatened by artemisinin resistance or aiming for malaria elimination. SLD-PQ may be beneficial in mass drug administration (MDA) campaigns to prevent malaria transmission but uptake is limited by concerns of hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The aim of this study was to improve the evidence on the safety of MDA with SLD-PQ in a sub-Saharan African setting. Methods A nonlinear mixed-effects model describing the pharmacokinetics and treatment-induced hemolysis of primaquine was developed using data from an adult (n = 16, G6PD deficient) and pediatric study (n = 38, G6PD normal). The relationship between primaquine pharmacokinetics and hemolysis was modeled using an established erythrocyte lifespan model. The safety of MDA with SLD-PQ was explored through Monte Carlo simulations for SLD-PQ at 0.25 or 0.4 mg/kg using baseline data from a Tanzanian setting with detailed information on hemoglobin concentrations and G6PD status. Results The predicted reduction in hemoglobin levels following SLD-PQ was small and returned to pre-treatment levels after 25 days. G6PD deficiency (African A- variant) was associated with a 2.5-fold (95% CI 1.2–8.2) larger reduction in hemoglobin levels. In the Tanzanian setting where 43% of the population had at least mild anemia (hemoglobin < 11–13 g/dl depending on age and sex) and 2.73% had severe anemia (hemoglobin < 7–8 g/dl depending on age and sex), an additional 3.7% and 6.0% of the population were predicted to develop at least mild anemia and 0.25% and 0.41% to develop severe anemia after 0.25 and 0.4 mg/kg SLD-PQ, respectively. Children < 5 years of age and women ≥ 15 years of age were found to have a higher chance to have low pre-treatment hemoglobin. Conclusions This study supports the feasibility of MDA with SLD-PQ in a sub-Saharan African setting by predicting small and transient reductions in hemoglobin levels. In a setting where a substantial proportion of the population had low hemoglobin concentrations, our simulations suggest treatment with SLD-PQ would result in small increases in the prevalence of anemia which would most likely be transient. Graphical abstract

Applying Historical Data in a Nonlinear Mixed-Effects Model Can Reduce the Number of Control Rats Required for Calculation of The Relative Potency of Insulin Analogues

This paper examines how to reduce the number of control animals in preclinical hyperinsulemic glucose clamp studies if we make use of information on historical studies. A data set consisting of 59 studies in rats to investigate new insulin analogues for diabetics, collected in the years 2000 to 2015, is analysed. A simulation experiment is performed based on a carefully built nonlinear mixed-effects model including historical information, comparing results (for the relative log-potency) with the standard approach ignoring previous studies. We find that by including historical information in the form of the mixed-effects model proposed, we can to remove between 23% and 51% of the control rats in the two studies looked closely upon to get the same level of precision on the relative log-potency as in the standard analysis. How to incorporate the historical information in the form of the mixed-effects model is discussed, where both a meta approach as well as a Bayesian approach are suggested. The conclusions are similar for the two approaches, and therefore, we conclude that the inclusion of historical information is beneficial in regard to using fewer control rats.

A Longitudinal Model-Based Biomarker Analysis of Exposure Response in Adults with Pulmonary Tuberculosis

The identification of sensitive, specific and reliable biomarkers that can be quantified in the early phases of tuberculosis treatment and predictive of long-term outcome is key for the development of an effective short-course treatment regimen. Time-to-positivity (TTP), a biomarker of treatment outcome against Mycobacterium tuberculosis , measures longitudinal bacterial growth in Mycobacteria Growth Indicator Tube broth culture and may be predictive of standard time-to-stable-culture-conversion (TSCC). In two randomized phase 2b trials investigating dose-ranging rifapentine (Study 29 and 29x), 662 participants had sputum collected over six months where TTP, TSCC and time-to-culture-conversion were quantified. The goals of this post hoc study were to characterize longitudinal TTP profiles and to identify individual patient characteristics associated with delayed time to culture conversion. In order to do so, a nonlinear mixed-effects model describing longitudinal TTP was built. Independent variables associated with increased bacterial clearance (increased TTP), assessed by subject-specific and population-level trajectories, were higher rifapentine exposure, lower baseline grade of sputum acid-fast bacilli smear, absence of productive cough, and lower extent of lung infiltrates on radiographs. Importantly, sensitivity analysis revealed that major learning milestones in phase 2b trials, such as significant exposure-response and covariate relationships, could be detected using truncated TTP data as early as 6 weeks from start of treatment, suggesting alternative phase 2B study designs. The TTP model built depicts a novel phase 2B surrogate endpoint that can inform early assessment of experimental treatment efficacy and treatment failure or relapse in patients treated with shorter and novel TB treatment regimens, improving efficiency of phase 2 clinical trials.

Rationale of a lower dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on pharmacokinetic modelling

Context: Prenatal dexamethasone therapy is used in female foetuses with congenital adrenal hyperplasia to suppress androgen excess and prevent virilisation of the external genitalia. The traditional dexamethasone dose of 20 µg/kg/d has been used since decades without examination in clinical trials and is thus still considered experimental. Objective: Because the traditional dexamethasone dose potentially causes adverse effects in treated mothers and foetuses, we aimed to provide a rationale of a reduced dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on a pharmacokinetics-based modelling and simulation framework. Methods: Based on a published dexamethasone dataset a nonlinear mixed-effects model was developed describing maternal dexamethasone pharmacokinetics. In stochastic simulations (n=1000) a typical pregnant population (n=124) was split into two dosing arms receiving either the traditional 20 µg/kg/d dexamethasone dose or reduced doses between 5 and 10 µg/kg/d. Target maternal dexamethasone concentrations, identified from literature, served as threshold to be exceeded by 90% of mothers at steady state to ensure foetal hypothalamic‐pituitary‐adrenal axis suppression. Results: A two-compartment dexamethasone pharmacokinetic model was developed and subsequently evaluated to be fit for purpose. The simulations, including a sensitivity analysis regarding the assumed foetal:maternal dexamethasone concentration ratio, resulted in 7.5 µg/kg/d to be the minimum effective dose and thus our suggested dose. Conclusions: We conclude that the current experimentally used dexamethasone dose is 3-fold higher than needed, possibly causing harm in treated foetuses and mothers. The clinical relevance and appropriateness of our recommended dose should be tested in a prospective clinical trial.

Simplified Iohexol-Based Method for Measurement of Glomerular Filtration Rate in Goats and Pigs

The preclinical evaluation of novel therapies for chronic kidney disease requires a simple method for the assessment of kidney function in a uremic large animal model. An intravenous bolus of iohexol was administered to goats (13 measurements in n = 3 goats) and pigs (23 measurements in n = 5 pigs) before and after induction of kidney failure, followed by frequent blood sampling up to 1440 min. Plasma clearance (CL) was estimated by a nonlinear mixed-effects model (CLNLME) and by a one-compartmental pharmacokinetic disposition model using iohexol plasma concentrations during the terminal elimination phase (CL1CMT). A simple method (CLSM) for the calculation of plasma clearance was developed based on the most appropriate relationship between CLNLME and CL1CMT. CLSM and CLNLME showed good agreement (CLNLME/CLSM ratio: 1.00 ± 0.07; bias: 0.03 ± 1.64 mL/min; precision CLSM and CLNLME: 80.9% and 80.7%, respectively; the percentage of CLSM estimates falling within ±30% (P30) or ±10% (P10) of CLNLME: 53% and 12%, respectively). For mGFRNLME vs. mGFRSM, bias was −0.25 ± 2.24 and precision was 49.2% and 53.6%, respectively, P30 and P10 for mGFR based on CLSM were 71% and 24%, respectively. A simple method for measurement of GFR in healthy and uremic goats and pigs was successfully developed, which eliminates the need for continuous infusion of an exogenous marker, urine collection and frequent blood sampling.

The effect of Clofazimine Concentration on QT prolongation in patients treated for tuberculosis

Rationale Clofazimine is classified as a WHO group B drug for the treatment of rifampicin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several anti-tubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Objectives To describe the effect of clofazimine exposure on QT prolongation Methods Fifteen adults drug-susceptible tuberculosis patients received clofazimine mono-therapy as 300 mg daily for three days followed by 100 mg daily in one arm of a 2-week, multi-arm early bactericidal activity trial in South Africa. Pre-treatment Fridericia-corrected QT (QTcF) (105 patients, 524 ECGs) and QTcF’s from the clofazimine-monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Measurements and Main Results Clofazimine was associated with significant QT prolongation described by an Emax function. We predicted clofazimine exposures using 100-mg daily doses and two-weeks loading with 200 and 300 mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (ΔQTcF>30) were 2.52%, 11.6%, and 23.0% for 100, 200, and 300-mg daily doses, respectively. At steady state, the expected proportion with ΔQTcF>30 ms was 23.7% and for absolute QTcF>450 ms was 3.42% for all simulated regimens. Conclusions The use of loading doses of 200 and 300 mg is not predicted to expose patients to increased risk of QT prolongation, compared to the current standard treatment, and is, therefore, an alternative option to achieve therapeutic concentrations faster.

Modeling Between-Subject Variability in Subcutaneous Absorption of a Fast-Acting Insulin Analogue by a Nonlinear Mixed Effects Approach

Despite the great progress made in insulin preparation and titration, many patients with diabetes are still experiencing dangerous fluctuations in their blood glucose levels. This is mainly due to the large between- and within-subject variability, which considerably hampers insulin therapy, leading to defective dosing and timing of the administration process. In this work, we present a nonlinear mixed effects model describing the between-subject variability observed in the subcutaneous absorption of fast-acting insulin. A set of 14 different models was identified on a large and frequently-sampled database of lispro pharmacokinetic data, collected from 116 subjects with type 1 diabetes. The tested models were compared, and the best one was selected on the basis of the ability to fit the data, the precision of the estimated parameters, and parsimony criteria. The selected model was able to accurately describe the typical trend of plasma insulin kinetics, as well as the between-subject variability present in the absorption process, which was found to be related to the subject’s body mass index. The model provided a deeper understanding of the insulin absorption process and can be incorporated into simulation platforms to test and develop new open- and closed-loop treatment strategies, allowing a step forward toward personalized insulin therapy.

Population Pharmacokinetic and Pharmacodynamic Target Attainment Analysis of Cefazolin in the Serum and Hip Joint Capsule of Patients Undergoing Total Hip Arthroplasty

The objectives of this study were to evaluate the population pharmacokinetics of prophylactic cefazolin (CFZ) from its serum and hip joint capsule concentrations in patients undergoing total hip arthroplasty, and to establish pharmacodynamic target concentration exceeding the MIC for designing an effective dosing regimen for serum and the hip joint capsule. We analyzed 249 serum samples and 125 hip joint capsule samples from 125 individuals using a nonlinear mixed-effects model. The pharmacodynamic index target value obtained from our results indicates the probability of maintaining CFZ trough and hip joint capsule concentrations exceeding the MIC of 1 mg/L, to account for methicillin-susceptible S. aureus (MSSA). We estimated the population pharmacokinetics using a two-compartment model. The estimated population pharmacokinetic parameters were as follows: CL (L/h) = 1.46 × (CLcr (mL/min)/77)0.891, Vc (L) = 7.5, Q (L/h) = 3.38, and VJC (L) = 36.1. The probability of achieving concentrations exceeding the MIC90 for MSSA was approximately 100% for serum and 100% for the hip joint capsule at 3 h after the initial dose. Our findings suggest that population-based parameters are useful for evaluating CFZ pharmacokinetics and that individual dosages should be determined based on the dosage regimen that achieves and maintains adequate tissue CFZ concentration.