Population pharmacokinetics of acyclovir in children with malignancy

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Background: Acyclovir exhibits a selective inhibition of herpes virus replication with potent clinical antiviral activity against the herpes simplex and varicella-zoster virus (King & Madera, 1988).Valacyclovir, a pro-drug of acyclovir, increases the oral bioavailability of acyclovir (Soul-Lawton et al. 1995). Acyclovir is primarily renally eliminated. Acyclovir displays variability in treatment response which supports the need for individualised dose regimens to optimize clinical outcomes. The aim of this study is to characterise the pharmacokinetics of acyclovir following intravenous infusion of acyclovir and oral administration of valacyclovir in children, and to investigate patient factors which contribute to inter-individual patient variability (IIV) in acyclovir pharmacokinetics.

Methods: Acyclovir or valacyclovir (5 mg/kg or 10 mg/kg) was administered as a 1 h intravenous infusion or oral dose, respectively. A total of 1216 plasma samples was collected from 43 children with malignancy (age: 9.2 months – 19.95 years), and acyclovir concentrations were analysed using a validated HPLC method. A nonlinear mixed effect modelling approach implemented in the NONMEM (Ver 5.1.1) software was employed to analyse acyclovir pharmacokinetic data using first order conditional estimation with interaction (FOCEI), an exponential random effects model used to describe IIV and a combined exponential and additive error model to estimate the residual unexplained error. Patient covariates, including weight (WT; kg), weight with an allometric scalling function (WT0.75, kg), estimated creatinine clearance (CLCR; L/h; using Counahan equation (Counahan et al. 1976)), body surface area (BSA, m2), body mass index (BMI, kg.m-2), glomerular filtration rate (GFR, L/h; determined by measuring the plasma clearance of 43Tc99 – diethylenetriaminepentacetic acid) and height (HT, cm) were screened for significant (p<0.01) relationships with pharmacokinetic parameters, then incorporated into the model in a forward stepwise manner followed by backwards elimination. The NONMEM generated objective function value (OFV) and diagnostic plots were used in the pharmacokinetic model selection process.

Results: Acyclovir concentration-time data were best described by a two-compartment pharmacokinetic model with first order elimination. The population mean estimates of clearance (CL), volume of distribution in the central compartment (V1), absorption rate (ka), bioavailability (F), inter-compartmental clearance (Q) and volume of distribution in the peripheral compartment (V2) were 3.15 L/h, 7.06 L, 0.66 (h-1), 0.59, 0.32 L/h and 318 L, respectively, and IIV were 25% for CL, 40% for V1, 62% for ka, 42% for F, respectively. The model building process identified a number of important covariate relationships with pharmacokinetic parameter which are described as follows:

CL (L/h) =3.15 × (WT/19.6)0.75 × (CLCR/3.04)0.34

V1 (L) =7.06 × (WT/19.6)

Q (L/h) =0.32 × (WT/19.6)0.75

Conclusions: A population pharmacokinetic model for acyclovir in children with malignancy has been developed and evaluated. Weight with an allometric scaling function and CLCR significantly contributed to variability in acyclovir CL, while weight with an allometric scaling function significantly influenced V1. With information about the concentration-effect relationship for acyclovir in children with malignancy these data can be used in the design of rational dosing strategies for acyclovir antivirus therapy.

References:

  1. Counahan R et al. Arch. Dis. Child. 1976 51: 875-8.
  2. King DH, Madera C. J. Am. Acad. Dermatol.1988 18: 176-9.
  3. Soul-Lawton J et al. Antimicrob. Agents Chemother.1995 39: 2759-64.
2008