Prospective, Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

Abstract

cThe current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normalweight patients were enrolled, with mean body mass indexes of 45. 2 ) in the United States and an additional 34% as overweight (BMI, Ͻ30 but Ն25 kg/m 2 ). Class III obesity (BMI, Ն40 kg/m 2 ) has risen from 1.3% in the 1980s to 6.6% currently (1). Body composition is a major factor influencing drug pharmacokinetics (PK) and can alter several parameters, including volume of distribution (V) and clearance (CL) (2). Unfortunately, published PK data specific to obese patients are limited. While biomarkers and surrogate endpoints can direct dosing of certain agents, such as antihypertensives and lipid-lowering drugs, no such biomarkers exist for antimicrobials; thus, clinicians must rely on published PK and pharmacodynamic (PD) data.Acyclovir is a nucleoside analogue that possesses activity against the herpes family of viruses, including herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV) (3). The efficacy of acyclovir for treating HSV has been linked to both area under the plasma concentration-time curve (AUC) and the time that drug concentration remains above the 50% inhibitory concentration (TϾIC 50 ) (4-7). The TϾIC 50 target that has been proposed is 50% of the dosing interval (4-9). Controversy exists regarding which of these PD parameters is most important in predicting clinical success.The manufacturer recommends calculation of intravenous (i.v.) acyclovir dose to be based on total body weight (TBW); however, in obese patients it recommends dosing by ideal body weight (IBW) (3). The only literature to support this recommendation is a single PK analysis comparing morbidly obese (MO) to normal-weight (NW) healthy females, presented as an abstract in 1991 by Davis and colleagues (10). All participants received doses based on TBW. Dosing by TBW in MO patients resulted in approximately 2-fold-higher maximum concentrations than in NW patients. The authors concluded that dosing by TBW in MO patients was inappropriate and recommended the use of IBW in this population (10). The conclusions of this study remain to be validated. The decision to not use TBW in dosing morbidly obese patients is supported by at least one case of an obese patient developing acyclovir-induced renal failure following i.v. acyclovir dosed by TBW (11). A prospective evaluation of IBW to dose a...

Acute Renal Failure Related to High Doses of Acyclovir (15 mg/kg/8 h) during Treatment of Varicella Zoster Virus Encephalitis

“…In our study, both patients presented a weight over 80 kg and were overweight, but not obese (BMI >25<30) and acyclovir was thus not administered at the dosage recommended for the ideal body weight (IBW). However, the precise optimal regimen for use in obese patients remains unclear and use of IBW can lead to lower systemic exposure [19]. In our two cases, the patients presented clinical improvement without toxicity at initial doses of 10 mg/kg/8 h and thus the increase to 15 mg/kg/8 h is questionable.…”

Impact of Obesity on Acyclovir-Induced Nephrotoxicity

“…An abstract presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy in 1991 suggested that morbidly obese patients should be dosed according to IBW based upon excessive acyclovir concentrations in 7 morbidly obese vs 5 normal-weight patients utilizing ABW [4]. Conversely, Turner and colleagues evaluated IBW dosing of acyclovir in 14 patients, 7 of whom were morbidly obese, and determined that systemic exposure in the morbidly obese patients provided substantially lower exposure than that of the nonobese patients [13]. Although obesity was a risk factor for toxicity in our study, we did not observe a difference in the rates of acyclovir-associated nephrotoxicity regardless of weight utilized for dosing calculations.…”

Dosing Practices of Intravenous Acyclovir for Herpes Encephalitis in Obesity: Results of a Pharmacist Survey

“…It should be noted that this recent pharmacokinetic study was presented at an international meeting after the results of our survey were collected. 13 Standardization of acyclovir dosing in obesity may help to optimize patient outcomes. Our study has several limitations.…”

“…1 Recent data, however, suggest that the use of IBW in obese patients results in significantly lower systemic exposure than in normal weight patients dosed using ABW. 13 This raises concern that using IBW as the dosing weight in the obese leads to underdosing. Given the known potential for long-term sequelae and neurological deficits after therapy for HSV encephalitis, the concern for underdosing coupled with concerns for overdosing and nephrotoxicity may lead to inconsistencies in the dosing of intravenous acyclovir.…”