Background: Determination of optimal doses for obese patients is challenging due to the paucity of clear dosing guidelines for this population. Empirical dosing strategies based on total body weight (WT) may result in overdoses in the obese, whereas arbitrary dose capping by physicians may produce sub-therapeutic concentrations. Quantifying the impact of obesity on drug clearance using an appropriate size descriptor will enable more accurate predictions about the dose-exposure-response relationship in the obese, thus improving therapeutic outcomes.
Aim: To assess the impact of obesity on drug clearance
Methods: We hypothesised that lean body weight (LBW) [1] can adequately predict drug exposure by taking into account changes in body composition that occur with obesity. The hypothesis states that (1) absolute clearance is greater in obese individuals, (2) clearance increases nonlinearly with WT, and (3) clearance correlates linearly with LBW [2]. This hypothesis was tested for renal and hepatic clearance pathways using inulin [3] and fentanyl [4] respectively. A further 72 studies were identified that examined the influence of obesity on drug clearance.
Results: Assessment of renal filtration showed that inulin clearance was 42% greater in the obese than non-obese (P=0.003), 36% lower when standardised by WT (P=0.002), and not significantly different when standardised by LBW (P=0.27). Similarly, it was reported that hepatic clearance assessed using fentanyl was higher in obese patients, lower when standardised by WT, and not significantly different when standardised to an empirically-derived size metric termed PK mass. PK mass was found to be linearly correlated with LBW (R2=0.92 for males, R2=0.94 for females). Of the 72 studies identified, only 5 studies considered LBW as a covariate, with the remainder using either ideal body weight or body mass index. All but 3 studies indirectly supported at least 1 of our hypothesised tenets, thus providing empirical support that body composition is sufficient to explain part of the predictable component of between subject variability in drug clearance.
Conclusion: We believe that the use of LBW as a covariate for clearance in pharmacokinetic studies will lead to improved insights into the influence of observable patient characteristics in the obese on drug exposure, thereby overcoming the limitations of empirical dosing strategies and ensuring optimal pharmacotherapy.
References:
- Janmahasatian et al. Clin Pharmacokinet 2005;44:1051-1065
- Han et al. Clin Pharmacol Ther 2007;82:505-508
- Janmahasatian et al. Br J Clin Pharmacol 2007 (accepted)
- Shibutani et al. Anaesthesiology 2004;101:603-613