Glynn Morrish

The relationship between drug clearance and body size: systematic review and meta-analysis of the literature published from 2000 to 2007

AbstractBackground: A variety of body size covariates have been used in population pharmacokinetic analyses to describe variability in drug clearance (CL), such as total body weight (TBW), body surface area (BSA), lean body weight (LBW) and allometric TBW. There is controversy, however, as to which body size covariate is most suitable for describing CL across the whole population. Given the increasing worldwide prevalence of obesity, it is essential to identify the best size descriptor so that dosing regimens can be developed that are suitable for patients of any size. Aim: The aim of this study was to explore the use of body size covariates in population pharmacokinetic analyses for describing CL. In particular, we sought to determine if any body size covariate was preferential to describe CL and quantify its relationship with CL, and also identify study design features that result in the identification of a nonlinear relationship between TBW and CL. Methods: Population pharmacokinetic articles were identified from MEDLINE using defined keywords. A database was developed to collect information about study designs, model building and covariate analysis strategies, and final reported models for CL. The success of inclusion for a variety of covariates was determined. A meta-analysis of studies was then performed to determine the average relationship reported between CL and TBW. For each study, CL was calculated across the range of TBW for the study population and normalized to allow comparison between studies. BSA, LBW, and allometric TBW and LBW relationships with exponents of 3/4, 2/3, and estimated values were evaluated to determine the relationship that best described the data overall. Additionally, joint distributions of TBW were compared between studies reporting a ‘nonlinear’ relationship between CL and TBW (i.e. LBW, BSA and allometric TBW-shaped relationships) and those reporting ‘other’ relationships (e.g. linear increase in CL with TBW, ideal body weight or height). Results: A total of 458 out of 2384 articles were included in the analysis, from which 484 pharmacokinetic studies were reviewed. Fifty-six percent of all models for CL included body size as a covariate, with 52% of models including a nonlinear relationship between CL and TBW. No single size descriptor was more successful than others for describing CL. LBW with a fixed exponent of 2/3, i.e. (LBW/50.45)2/3, or estimated exponent of 0.646, i.e. ∼2/3, was found to best describe the average reported relationship between CL and TBW. The success of identifying a nonlinear increase in CL with TBW was found to be higher for those studies that included a wider range of subject TBW. Conclusions: To the best of our knowledge, this is the first study to have performed a meta-analysis of covariate relationships between CL and body size. Although many studies reported a linear relationship between CL and TBW, the average relationship was found to be nonlinear. LBW with an allometric exponent of ∼2/3 may be most suitable for describing an increase in CL with body size as it accounts for both body composition and allometric scaling principles concerning differences in metabolic rates across size.

The effects of obesity on drug pharmacokinetics in humans

Introduction: The prevalence of obesity and associated co-morbid conditions is increasing globally. Physiological changes accompanying obesity are likely to result in altered drug pharmacokinetics; however, there is paucity of information on how to best dose adjust for the obese. Areas covered: This review presents material describing physiological changes that occur in the obese and their relationship to body composition. The review also discusses various dosing metrics currently used to scale for size, and relationships between body composition and pharmacokinetic parameters. Through this, the reader is provided with a greater understanding of the key concepts regarding the physiological changes associated with obesity and how they relate to the changes in the pharmacokinetics. Expert opinion: There is a nonlinear relationship between total body weight and the physiological variables that determine drug clearance. Metrics that describe pharmacokinetics at the extremes of weight in a semi-mechanistic manner should be used as drug dosing scalars, with clinical trials adequately designed to correctly identify the most appropriate dosing scalar.

Leveraging physiological data from literature into a pharmacokinetic model to support informative clinical study design in pregnant women.

PurposePhysiological changes during pregnancy can effect pharmacokinetic (PK) parameters, which may lead to altered dose requirements. We aimed to leverage literature-based physiological changes during pregnancy into a PK model and compare its performance to a published reference model in pregnant women and to use the literature-based model to determine informative PK sampling times for a clinical study that aims to quantify the PK of enoxaparin throughout pregnancy.MethodsChanges in total body water (BW) and creatinine clearance (CRCL) during pregnancy were described using regression models. BW and CRCL were linked to a PK model of enoxaparin in non-pregnant women. Performance of the literature-based PK model was compared to a previously published empirical reference model. D-optimal sampling times were determined and evaluated for literature-based and reference models.ResultsThe literature-based model adequately predicted anti-Xa plasma concentrations when compared to reference model predictions. An informative sampling design was succesfully developed, with parameters expected with good precision (RSE < 36.4%).ConclusionA literature-based model describing enoxaparin PK during pregnancy was developed and evaluated. The modelling framework could be used to support development of informative designs in pregnancy when prior models are unavailable.

Pharmacokinetics and Pharmacodynamics of Etravirine 400 mg Once Daily in Treatment-Naïve Patients

Abstract Background: Etravirine is currently approved for HIV treatment–experienced patients at a dose of 200 mg twice daily. The long terminal elimination half-life of etravirine should support once-daily dosing.Methods: In the double-blind 48-week SENSE trial, 157 antiretroviral treatment–naïve patients were randomly assigned to receive etravirine 400 mg once daily (n = 79) or efavirenz 600 mg once daily (n = 78), plus 2 nucleoside reverse transcriptase inhibitors (NRTIs). Sparse sampling for etravirine plasma concentrations was conducted during the 48-week trial. Area under the curve over the dosing interval (AUC24) and trough concentration (C0) were estimated using a population pharmacokinetic model and compared with previous results using the 200-mg twice-daily dosage. The relationship between etravirine AUC24 and C0 with efficacy and safety was also assessed.Results: By week 48, the percentage of patients in the etravirine arm with HIV RNA <50 copies/ mL was 75.9% in the intent-to-treat switch equals failure analysis and 92.3% in the on-treatment analysis; no patient developed genotypic or phenotypic resistance to NRTIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs) after virologic failure. Seventy-one subjects had evaluable etravirine pharmacokinetics. The median (interquartile range) of etravirine AUC24 and C0 were 12,447 (8,261–15,652) ng•h/mL and 330 (188–472) ng/mL, respectively. There was no correlation between etravirine exposure and virologic response or adverse events.Conclusions: In the SENSE trial, etravirine 400 mg once daily achieved similar exposures to historical reference data on etravirine when dosed at 200 mg twice daily. There was no apparent relationship between the pharmacokinetics of etravirine and virologic response or adverse events.

Noninvasive Quantification of Hepatic Steatosis: Relationship Between Obesity Status and Liver Fat Content

The aim of this study was to assess and compare fat content within the liver for normal (body mass index (BMI) < 25 kg/m 2 ), overweight (25-30 kg/m 2 ) and obese (� 30 kg/m 2 ) subjects using a noninvasive, non-contrast computed tomography (CT) quantification method. Adult subjects aged 18-60 yrs scheduled to undergo CT examination of the abdominal region were recruited for this study, stratified across BMI categories. Liver volume, fat content, and lean liver volume were determined using CT methods. A total of 100 subjects were recruited, including 30 normal weight, 31 overweight, and 39 obese. Total liver volume increased with BMI, with mean values of 1138 ± 277, 1374 ± 331, and 1766 ± 389 cm 3 for the normal, overweight, and obese, respectively (P < 0.001), which was due to an increase in both liver fat content and lean liver volume with BMI. Some obese subjects had no or minimal hepatic fat content. The prevalence of mild fatty liver in this study of 100 subjects was overestimated for all BMI categories using a range of qualitative diagnostic measures, with predicted prevalence of fatty liver in obese subjects ranging from 76.9% for liver-to-spleen ratio � 1.1 to 89.7% for liver attenuation index (liver HU - spleen HU) � 40, compared to 66.7% by quantification of fat content. Results show that total liver volume increases with BMI, however, not all obese subjects display fatty infiltration of the liver. CT quantification of liver fat content may be suitable for accurate diagnosis of hepatic steatosis in clinical practice and assessment of donor livers for transplantation.