Integrated pharmacokinetic-pharmacodynamic model for acetaminophen, ibuprofen, and placebo antipyresis in children

A descriptive profile for antipyretic drug action has been documented for c hildren. However, a linked pharmacokinetic-pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile childre n. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg). ibup rofen (IBU) (5 or 10,mg/kg), or placebo. Rectal temperatures and plasma lev els (mu g/ml) of APAP and IBU were measured for up to 12 hr after drug admi nistration Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, li nk, and Sigmoid E-max effect model in 102/153 febrile children given APAP o r IBU The PK parameters (t(lag), k(a), beta, T-1/(2 beta), AUC(0-infinity), V-d/F, and Cl-p/F) were not different than those reported previously, exce pt the APAP k(a) was significantly lower. The link component yielded k(eo)s of 0.58 +/- 0.06 ((x) over bar +/- SE), 0.70 +/- 0.11 and 0.57 +/- 0.11 hr (-1) for APAP, IBU05, and IBU10, respectively: the Sigmoid E-max component yielded EC(50)s (mu g/ml) and sig-moidicity (gamma) of 4.63 +/- 0.39 and 3. 98 +/- 0.42 for APAP, 11.33 +/- 1.35 and 3.97 +/- 0.58 for IBU05 and 12.83 +/- 1.89 and 4.27 +/- 0.63 for IBU10. On visual inspection of the efficacy- time profiles of the febrile children, a number of them had an apparent lin ear function (slope: Delta degrees C/hr) and/or a sinusoidal cyclic functio n "confounding" standard approaches to PD analysis. Thus, the temperature p rofiles of 91/102 children given APAP or IBU required the addition of a slo pe (Delta degrees C/hr) and/or a sinusoidal cyclic function to the Sigmoid E-max component to fit the data satisfactorily. All 22 children given a pla cebo also required a slope and/or a cyclic function in their PD model. The residual Delta degrees Cs (observed-predicted) of the placebo group were no t significantly different from 0. Thus, no placebo antipyretic effect was o bserved. Dose dependency of IBU AUC(0-infinity) was confirmed; doubling the dose from 5 to 10 mg/kg increased the AUC(0-infinity) by only 1.5-fold. Th e confounding effect of initial temperature (Temp(i)) on antipyretic effica cy in all treatment groups except placebo was also confirmed to expose nonl inear pharmacodynamics. A significant (p = 0.03) contribution of Temp(i) (b ut not age) on the value of the slope function was found, There rc as no co nsistent effect of age or Temp(i) on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age a nd Temp(i) was observed with a large number of the PK, link, and PD variabl es in those who, received IBU. Dose, age, and Temp(i) interacted with beta in a significant multiple linear relationship with AUC(0-infinity). The eff ects of IBU dose, age, and Temp(i) are pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create t he slope function, the magnitude of which may be partially due to the under lying disease. In some cases, the cyclic function may be explained by tempe rature regulation. Regardless of their cause, both confound analysis of dru g action and make the simple, unmodified Sigmoid E-Max effect model less th an satisfactory for interpretation of antipyretic drug effects. The influence of Temp(i) oil the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medica tions. In children receiving IBU, dose and age are also confounders, in add ition to Temp(i). A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these;these antipyretics in febrile children.