Radojka M. Savic

Diagnosing Model Diagnostics

Conclusions from clinical trial results that are derived from model‐based analyses rely on the model adequately describing the underlying system. The traditionally used diagnostics intended to provide information about model adequacy have seldom discussed shortcomings. Without an understanding of the properties of these diagnostics, development and use of new diagnostics, and additional information pertaining to the diagnostics, there is risk that adequate models will be rejected and inadequate models accepted. Thus, a diagnosis of available diagnostics is desirable.

Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions

Empirical Bayes (“post hoc”) estimates (EBEs) of ηs provide modelers with diagnostics: the EBEs themselves, individual prediction (IPRED), and residual errors (individual weighted residual (IWRES)). When data are uninformative at the individual level, the EBE distribution will shrink towards zero (η-shrinkage, quantified as 1-SD(ηEBE)/ω), IPREDs towards the corresponding observations, and IWRES towards zero (ε-shrinkage, quantified as 1-SD(IWRES)). These diagnostics are widely used in pharmacokinetic (PK) pharmacodynamic (PD) modeling; we investigate here their usefulness in the presence of shrinkage. Datasets were simulated from a range of PK PD models, EBEs estimated in non-linear mixed effects modeling based on the true or a misspecified model, and desired diagnostics evaluated both qualitatively and quantitatively. Identified consequences of η-shrinkage on EBE-based model diagnostics include non-normal and/or asymmetric distribution of EBEs with their mean values (“ETABAR”) significantly different from zero, even for a correctly specified model; EBE–EBE correlations and covariate relationships may be masked, falsely induced, or the shape of the true relationship distorted. Consequences of ε-shrinkage included low power of IPRED and IWRES to diagnose structural and residual error model misspecification, respectively. EBE-based diagnostics should be interpreted with caution whenever substantial η- or ε-shrinkage exists (usually greater than 20% to 30%). Reporting the magnitude of η- and ε-shrinkage will facilitate the informed use and interpretation of EBE-based diagnostics.

Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies

Purpose: To compare the performance of the standard lag time model (LAG model) with the performance of an analytical solution of the transit compartment model (TRANSIT model) in the evaluation of four pharmacokinetic studies with four different compounds. Methods: The population pharmacokinetic analyses were performed using NONMEM on concentration–time data of glibenclamide, furosemide, amiloride, and moxonidine. In the TRANSIT model, the optimal number of transit compartments was estimated from the data. This was based on an analytical solution for the change in drug concentration arising from a series of transit compartments with the same first-order transfer rate between each compartment. Goodness-of-fit was assessed by the decrease in objective function value (OFV) and by inspection of diagnostic graphs. Results: With the TRANSIT model, the OFV was significantly lower and the goodness-of-fit was markedly improved in the absorption phase compared with the LAG model for all drugs. The parameter estimates related to the absorption differed between the two models while the estimates of the pharmacokinetic disposition parameters were similar. Conclusion: Based on these results, the TRANSIT model is an attractive alternative for modeling drug absorption delay, especially when a LAG model poorly describes the drug absorption phase or is numerically unstable.

Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption.

ABSTRACT This article describes the population pharmacokinetics of rifampin in South African pulmonary tuberculosis patients. Three datasets containing 2,913 rifampin plasma concentration-time data points, collected from 261 South African pulmonary tuberculosis patients aged 18 to 72 years and weighing 28.5 to 85.5 kg and receiving regular daily treatment that included administration of rifampin (450 to 600 mg) for at least 10 days, were pooled. A compartmental pharmacokinetic model was developed using nonlinear mixed-effects modeling. Variability in the shape of the absorption curve was described using a flexible transit compartment model, in which a delay in the onset of absorption and a gradually changing absorption rate were modeled as the passage of drug through a chain of hypothetical compartments, ultimately reaching the absorption compartment. A previously described implementation was extended to allow its application to multiple-dosing data. The typical population estimate of oral clearance was 19.2 liters·h−1, while the volume of distribution was estimated to be 53.2 liters. Interindividual variability was estimated to be 52.8% for clearance and 43.4% for volume of distribution. Interoccasional variability was estimated for CL/F (22.5%) and mean transit time during absorption (67.9%). The use of single-drug formulations was found to increase both the mean transit time (by 104%) and clearance (by 23.6%) relative to fixed-dose-combination use. A strong correlation between clearance and volume of distribution suggested substantial variability in bioavailability, which could have clinical implications, given the dependence of treatment effectiveness on exposure. The final model successfully described rifampin pharmacokinetics in the population studied and is suitable for simulation in this context.

Daily Rifapentine for Treatment of Pulmonary Tuberculosis. A Randomized, Dose-Ranging Trial

RATIONALE Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown. OBJECTIVES We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment. METHODS Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase. MEASUREMENTS AND MAIN RESULTS A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively). CONCLUSIONS Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).

Pharmacokinetics of Desmopressin Administrated as an Oral Lyophilisate Dosage Form in Children With Primary Nocturnal Enuresis and Healthy Adults

The population pharmacokinetics of desmopressin in children with nocturnal enuresis and in healthy adults were compared using a 1‐compartment model with first‐order absorption and first‐order elimination. In addition, the model consisted of a number of transit compartments before absorption to describe a lag‐time. The model gave an adequate description of adult as well as children data and provided a statistically significant better fit to data than a standard lag‐time model. The main difference in the pharmacokinetics between children and adults was the absorption delay. The pharmacokinetic difference was minor and presumably of no clinical relevance.

Semiparametric Distributions With Estimated Shape Parameters

PurposeTo investigate the use of adaptive transformations to assess the parameter distributions in population modeling.MethodsThe logit, box-cox, and heavy tailed transformations were investigated. Each one was used in conjunction with the standard (exponential) transformation for PK and PD parameters. The shape parameters of these transformations were estimated to allow the parameter distributions to more accurately resemble a wider range of parameter distributions. The transformations were tested both in simulated settings where the true distributions were known and in 30 models developed from real data.ResultsIn the simulated setting the transformations were better than the standard lognormal distribution at characterizing the true distributions. Improvement could also be seen in objective function value (OFV) and in simulation based diagnostics. In the real datasets, significant model improvement based on OFV could be seen in 22, 18, and 22 out of the 30 models for the three transformations respectively.ConclusionTransformations with estimated shape parameters are a promising approach to relax the often erroneous assumption of a known shape of the parameter distribution. They offer a simple and straightforward way of handling and characterizing parameter distributions.

Effect of adherence as measured by MEMS, ritonavir boosting, and CYP3A5 genotype on atazanavir pharmacokinetics in treatment-naive HIV-infected patients

We investigated population pharmacokinetics and pharmacogenetics of ritonavir‐boosted atazanavir (ATV), using drug intake times exactly recorded by the Medication Event Monitoring System. The ANRS 134–COPHAR 3 trial was conducted in 35 HIV‐infected treatment‐naive patients. ATV (300 mg), ritonavir (100 mg), and tenofovir (300 mg) + emtricitabine (200 mg), in bottles with MEMS caps, were taken once daily for 6 months. Six blood samples were collected at week 4 to measure drug concentrations, and trough levels were measured bimonthly. A model integrating ATV and ritonavir pharmacokinetics and pharmacogenetics used nonlinear mixed effects. Use of exact dosing data halved unexplained variability in ATV clearance. The ritonavir–ATV interaction model suggested that optimal boosting effect is achievable at lower ritonavir exposures. Patients with at least one copy of the CYP3A5*1 allele exhibited 28% higher oral clearance. We provide evidence that variability in ATV pharmacokinetics is defined by adherence, CYP3A5 genotype, and ritonavir exposure.

Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin.

One‐third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome‐wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator–activated receptor‐α and hepatocyte nuclear factor 4‐α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response.

Effect of Weight and Maturation on Busulfan Clearance in Infants and Small Children Undergoing Hematopoietic Cell Transplantation

Little information is currently available regarding the pharmacokinetics (PK) of busulfan in infants and small children to help guide decisions for safe and efficacious drug therapy. The objective of this study was to develop an algorithm for individualized dosing of i.v. busulfan in infants and children weighing ≤12 kg, that would achieve targeted exposure with the first dose of busulfan. Population PK modeling was conducted using intensive time-concentration data collected through the routine therapeutic drug monitoring of busulfan in 149 patients from 8 centers. Busulfan PK was well described by a 1-compartment base model with linear elimination. The important clinical covariates affecting busulfan PK were actual body weight and age. Based on our model, the predicted clearance of busulfan increases approximately 1.7-fold between 6 weeks to 2 years of life. For infants age <5 months, the model-predicted doses (mg/kg) required to achieve a therapeutic concentration at steady state of 600-900 ng/mL (area under the curve range, 900-1350 μM·min) were much lower compared with standard busulfan doses of 1.1 mg/kg. These results could help guide clinicians and inform better dosing decisions for busulfan in young infants and small children undergoing hematopoietic cell transplantation.