Adult age and <i>ex vivo</i> protein binding of lorazepam, oxazepam and temazepam in healthy subjects

Chin, Paul; Jensen, Berit Packert; Larsen, Helle S; Begg, Evan J.

doi:10.1111/j.1365-2125.2011.04036.x

Cited by 7 publications

(6 citation statements)

References 22 publications

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“…Sixty healthy subjects were recruited, including 10 males and 10 females in each of the groups 18–39, 40–64 and ≥65 years as described in Chin et al . [16]. Exclusion criteria included comorbidities, use of any medications in the last 7 days, pregnancy, current smoking, consumption of alcohol exceeding three (males) or two (females) standard drinks per day, or clinical or laboratory evidence of significant liver and renal disease.…”

Section: Methodsmentioning

confidence: 99%

Influence of adult age on the total and free clearance and protein binding of (R)‐ and (S)‐warfarin

Jensen

Chin

Roberts

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Hepatic drug clearance is thought to be reduced with age. However for highly protein bound drugs, which are cleared by capacity-limited metabolism, studies on total clearance have been conflicting. The hypothesis that protein binding decreases with age has been used to explain this.• Warfarin is a highly protein bound drug, which is cleared by capacity-limited metabolism. There are conflicting or little data on the relationship between adult age and total and free clearance and protein binding of (R)-and (S)-warfarin. WHAT THIS STUDY ADDS• In a clinical study of 72 patients (18-89 years) on warfarin therapy, both total and free clearance of (R)-warfarin decreased with age. For (S)-warfarin there was a stronger signal of a decrease in free than total clearance. Protein binding was found not to correlate with age for (R)-and (S)-warfarin.• In an ex vivo study, in which warfarin was spiked to plasma samples from 60 healthy subjects (19-87 years), no correlation between protein binding and age was found.• These data support the hypothesis that hepatic drug clearance decreases with age. This should be taken into consideration when individualizing dosing, particularly in the elderly. AIMSTo test the hypothesis that the clearance (CL) of warfarin, a very highly protein bound drug with capacity-limited metabolism, decreases with age. METHODSIn a clinical study, a steady-state blood sample was taken from 72 patients (18-89 years) on routine treatment with warfarin. Concentrations of (R)-and (S)-warfarin were determined in plasma (total) and ultrafiltrate (free) by LC-MS/MS. Total and free CL and protein binding were determined and regressed against age and other covariates. In an ex vivo study, warfarin was spiked to plasma samples from 60 healthy subjects (19-87 years) and protein binding was regressed against age and other covariates. RESULTSFor (R)-warfarin a significant decrease with age was found for both total and free CL (P < 0.001). For (S)-warfarin there was a stronger signal of a decrease with age in free CL (P = 0.005) vs. total CL (P = 0.045). The decrease in CL of (R)-and (S)-warfarin was 0.3-0.5% per year. Other covariates influencing CL were lean body weight for both (R)-and (S)-warfarin and CYP2C9 genotype and blood sampling time for (S)-warfarin. Protein binding of (R)-and (S)-warfarin was not found to change significantly with age in either the clinical or the spiked samples, despite a slight decrease in albumin concentration with age. CONCLUSIONSThese data support the hypothesis that the CL of (R)-and (S)-warfarin decreases with age. More accurate information was gained when measuring free CL for (S)-warfarin. Warfarin protein binding did not change significantly with age.

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Section: Methodsmentioning

confidence: 99%

Influence of adult age on the total and free clearance and protein binding of (R)‐ and (S)‐warfarin

Jensen

Chin

Roberts

et al. 2012

Brit J Clinical Pharma

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“…Another plausible explanation is the use of total drug concentration (bound + free drug) to estimate clearance (referred to as ‘total drug clearance’) . If clearance is exclusively metabolic, decreases in total drug clearance from reduced CL int.liver may be masked by increases in the free fraction in blood, which may occur for some, but not all drugs, in the elderly . This is illustrated hypothetically in Figure .…”

Section: Introductionmentioning

confidence: 99%

Predicted metabolic drug clearance with increasing adult age

Polasek

Patel

Jensen

et al. 2013

Brit J Clinical Pharma

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AIMTo determine the effect of increasing adult age on predicted metabolic drug clearance. METHODPredicted metabolic drug clearances (CLPT) were determined using in vitro-in vivo extrapolation coupled with physiological-based pharmacokinetic modelling and simulation (IVIVE-PBPK) in Simcyp®. Simulations were conducted using CYP-selective 'probe' drugs with subjects in 5 year age groups (20-25 to 90-95 years). CLPT values were compared with human pharmacokinetic data stratified according to age (young = 20-40 years and elderly = 65-85 years) and gender. Age-related changes in the physiological parameters used for IVIVE of CLPT were described. RESULTSPredicted metabolic drug clearances decreased with increasing adult age to approximately 65-70 years: caffeine from 1.5 to 1.0 ml min(a 33% decrease), S-warfarin from 0.100 to 0.064 ml min -1 kg -1 (36%), S-mephenytoin from 4.1 to 2.5 ml min -1 kg -1 (39%), desipramine from 10.6 to 7.3 ml min -1 kg -1 (31%) and midazolam from 5.4 to 3.9 ml min -1 kg -1 (27%). Except for S-mephenytoin, predictions were within 3.5-fold of clearances from clinical studies when stratified by age and gender. A trend towards higher CLPT was observed in females, but this was only statistically significant in larger virtual trials. Physiological parameters that determine CLPT decreased with increasing adult age: mean microsomal protein g -1 of liver, liver weight, hepatic blood flow and human serum albumin concentration. CONCLUSIONDecreased metabolic clearance in the elderly was predicted by Simcyp® and was generally consistent with limited clinical data for four out of five drugs studied and the broader literature for drugs metabolized by CYP enzymes. IVIVE-PBPK may be increasingly useful in predicting metabolic drug clearance in the elderly. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The clearance of drugs metabolized by CYP enzymes is decreased in the elderly.• In vitro-in vivo extrapolation coupled with physiological-based pharmacokinetic (IVIVE-PBPK) modelling and simulation is used widely to predict metabolic drug clearance. WHAT THIS STUDY ADDS• Similar to the broad body of clinical literature for drugs metabolized by CYP enzymes, IVIVE-PBPK modelling and simulation using Simcyp® predicts decreased weight-normalized metabolic clearance of 20-40% in the elderly. • This prediction is a direct consequence of age-related decreases in the physiological parameters used for IVIVE of metabolic drug clearance; mean microsomal protein g -1 of liver, liver weight, hepatic blood flow and human serum albumin concentration.• Predictions of decreased metabolic drug clearance with increasing adult age are similar for drugs with different hepatic extraction ratios and protein binding characteristics, and appear to be independent of drug-specific physiochemical parameters, the CYP enzymes responsible for metabolism and their fractional contribution to metabolic clearance. • Decreased clearance in the elderly may be similar for all drugs eliminated exclusively by CYP enzymes.

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“…The authors successfully predicted the fraction of protein binding in infants for several compounds using fraction unbound in adults and compound-specific plasma protein affinity. For lorazepam, literature data indicate an affinity for albumin and an average fraction unbound (plasma) of 0.11 in adults (11)(12)(13).…”

Section: Age-dependent Scaling Of Pbpk Model Parametersmentioning

confidence: 99%

“…Most published literature regarding lorazepam PK parameters (Table I) is primarily focused on an adult patient population. In humans, lorazepam exhibits an affinity for albumin with a bound fraction in plasma of approximately 89% (11)(12)(13). Hepatic metabolism and renal filtration represent the major and minor pathways of clearance, respectively (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

A Workflow Example of PBPK Modeling to Support Pediatric Research and Development: Case Study with Lorazepam

Maharaj

Barrett

Edginton

2013

AAPS J

105

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Abstract. The use of physiologically based pharmacokinetic (PBPK) models in the field of pediatric drug development has garnered much interest of late due to a recent Food and Drug Administration recommendation. The purpose of this study is to illustrate the developmental processes involved in creation of a pediatric PBPK model incorporating existing adult drug data. Lorazepam, a benzodiazepine utilized in both adults and children, was used as an example. A population-PBPK model was developed in PK-Sim v4.2® and scaled to account for age-related changes in size and composition of tissue compartments, protein binding, and growth/maturation of elimination processes. Dose (milligrams per kilogram) requirements for children aged 0-18 years were calculated based on simulations that achieved targeted exposures based on adult references. Predictive accuracy of the PBPK model for producing comparable plasma concentrations among 63 pediatric subjects was assessed using average-fold error (AFE). Estimates of clearance (CL) and volume of distribution (V ss ) were compared with observed values for a subset of 15 children using fold error (FE). Pediatric dose requirements in young children (1-3 years) exceeded adult levels on a linear weight-adjusted (milligrams per kilogram) basis. AFE values for model-derived concentration estimates were within 1.5-and 2-fold deviation from observed values for 73% and 92% of patients, respectively. For CL, 60% and 80% of predictions were within 1.5 and 2 FE, respectively. Comparatively, predictions of V ss were more accurate with 80% and 100% of estimates within 1.5 and 2 FE, respectively. Using the presented workflow, the developed pediatric model estimated lorazepam pharmacokinetics in children as a function of age.

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Adult age and ex vivo protein binding of lorazepam, oxazepam and temazepam in healthy subjects

Cited by 7 publications

References 22 publications

Influence of adult age on the total and free clearance and protein binding of (R)‐ and (S)‐warfarin

Influence of adult age on the total and free clearance and protein binding of (R)‐ and (S)‐warfarin

Predicted metabolic drug clearance with increasing adult age

A Workflow Example of PBPK Modeling to Support Pediatric Research and Development: Case Study with Lorazepam

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