Current data on mycophenolate mofetil (MMF) suggest that there is a pharmacokinetic/pharmacodynamic relationship between the mycophenolic acid (MPA) area under the curve (AUC) during treatment and both the risk of acute rejection and the occurrence of side effects. The aim of this study was to characterize the population pharmacokinetics of MPA in kidney transplant patients between the ages of 2 and 21 years and to propose a limited sampling strategy to estimate individual MPA AUCs. Forty-one patients received long-term oral MMF continuous therapy as part of a triple immunosuppressive regimen, which also included cyclosporine or tacrolimus (n=3) and corticosteroids. Therapy was initiated at a dose of 600 mg/m twice daily. The population parameters were calculated from an initial group of 32 patients. The data were analyzed by nonlinear mixed-effect modeling using a 2-compartment structural model with first-order absorption and a lag time. The interindividual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Fifteen concentration-time profiles from 13 patients were used to evaluate the predictive performance of the Bayesian approach and to devise a limited sampling strategy. The protocol, involving two sampling times, 1 and 4 hours after oral administration, allows the precise and accurate determination of MPA AUCs (bias -0.9 microg.h/mL; precision 6.02 microg.h/mL). The results of this study combine the relationships between the pharmacokinetic parameters of MPA and patient covariates, which may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.

The aim of the present study was to characterize the population pharmacokinetics of ciprofloxacin in patients with and without cystic fibrosis ranging in age from 1 day to 24 years and to propose a limited sampling strategy to estimate individual pharmacokinetic parameters. Patients were divided into four groups according to the treatment schedule. They received ciprofloxacin by intravenous infusion (30 min) or by the oral route. The number of samples collected from each patient ranged from 1 to 12. The population parameters were computed for an initial group of 37 patients. The data were analyzed by nonlinear mixed-effect modeling by use of a two-compartment structural model. The interindividual variability in clearance (CL) was partially explained by a dependence on age and the patient's clinical status. In addition, a significant relationship was found between weight and the initial volume of distribution. Eighteen additional patients were used for model validation and evaluation of limited sampling strategies. When ciprofloxacin was administered intravenously, sampling at a single point (12 h after the start of infusion) allowed the precise and accurate estimation of CL and the elimination half-life, as well as the ciprofloxacin concentration at the end of the infusion. It should be noted that to take into account the presence of a lag time after oral administration, a schedule based on two sampling times of 1 and 12 h is needed. The results of this study combine relationships between ciprofloxacin pharmacokinetic parameters and patient covariates that may be useful for dose adjustment and a convenient sampling procedure that can be used for further studies.Hospitalized pediatric patients with serious infections are a challenge to the clinician who takes care of them. Indeed, the pharmacokinetics of most drugs are age dependent (4,8,32). Maturation of metabolic pathways takes place at different rates; the level of metabolic clearance of drugs is very low at birth and then increases to reach a maximum at about age 1 year, when it can exceed that for adults. Renal blood flow, the glomerular filtration rate, and tubular secretion are all lower at birth and then increase to approach the values for adults by the end of the first year of life. There are also significant changes in drug disposition and in the quantity and quality of plasma proteins in the first few years of life. Moreover, pharmacoki-

The objective of the present study was to develop a population pharmacokinetic model for nelfinavir mesylate (NFV) and nelfinavir hydroxy-tert-butylamide (M8), the most abundant metabolite of NFV, in infants vertically infected with human immunodeficiency virus type 1 and participating in the Paediatric European Network for Treatment of AIDS 7 study. Plasma NFV concentrations were determined during repeated NFV administrations (two to three times a day). Eighteen infants younger that age 2 years participated in this study. The doses administered ranged from 71 to 203 mg/kg of body weight/day. Pharmacokinetic parameter estimates were obtained by a compartmental approach by using a kinetic model to simultaneously fit NFV and M8 (active metabolite) concentrations. M8 was shown to be formation rate limited and was characterized by first-order rate constants of formation and elimination. Body weight was found to be a more appropriate predictor than age of the changes in (i) the rate of metabolism, (ii) the elimination rate constant of NFV, and (iii) NFV clearance. Population parameters were computed to account for the relationship between the rate of metabolism and body weight. The estimated NFV and M8 elimination half-lives were 4.3 and 2.04 h, respectively. The estimated NFV clearance was 2.13 liters/h/kg. The M8 concentration-to-NFV concentration ratio was 0.64 ؎ 0.44. In conclusion, the population pharmacokinetic model describing the dispositions of NFV and M8 should facilitate the design of future studies to elucidate the relative contributions of the parent compound and M8 to the pharmacological and toxic effects of NFV therapy.The introduction of protease inhibitors in clinical practice has caused an impressive decrease in the rates of morbidity and mortality among patients infected with human immunodeficiency virus (HIV) (5, 11). Although it is still not clear when antiretroviral treatment should be initiated in children, treatment in the first months of life is an important option to be considered when symptoms are present or the CD4-cell count is low (23). Nowadays, the standard of care for the treatment of HIV type 1 (HIV-1) infection includes two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with one or two protease inhibitors or a nonnucleoside reverse transcriptase inhibitor (8,10,15).Nelfinavir mesylate (NFV) is a nonpeptidic protease inhibitor (18) approved for use by the Food and Drug Administration in March 1997 for the treatment of HIV-1-infected children. Like other such agents, it prevents cleavage of the HIV-1 Gag and Gap-Pol precursor polyproteins by the protease, resulting in the production of immature, noninfectious virus particles. NFV is available in both tablet and powder formulations; after oral administration, the plasma NFV concentrations have been found to be similar for these two formulations (7). The powder formulation can feasibly be given to newborn infants. However, little is known about the safety and pharmacokinetics of NFV in this population (3,4,7,9,13,16,...

Nelfinavir mesylate (NFV) is a nonpeptidic inhibitor of the human immunodeficiency virus type 1 protease (HIV‐1). This drug is metabolized through CYP2C19 (a cytochrome P450 isoenzyme) to form the hydroxy‐tert‐butylamide (M8), the most abundant metabolite of NFV. This metabolite appears to have in vitro antiviral activity comparable with that of the parent drug. Few studies have been performed to evaluate the pharmacokinetics of NFV and its active metabolite in a pediatric population. The objective of this study was to develop a population pharmacokinetic model for NFV and M8 in a population of children younger than 2 years of age vertically infected with HIV‐1. Plasma concentrations were obtained during repeated NFV administrations (two to three‐time a day) in 22 infants (1.5–16.3 months). The initial administered dose ranged from 81 to 200 mg/kg/day. Pharmacokinetic parameter estimates were obtained by compartmental methods to describe the disposition of metabolite that is dependent on the disposition of the parent compound. M8 was shown to be formation rate‐limited and was characterized by first‐order rate constants of formation and elimination. Because the fraction of the NFV dose metabolized to M8 (FM) was unknown in this patient population, the volume of distribution divided by FM was estimated for M8. Estimated NFV and M8 elimination half‐lives were 2.83 and 1.87 h, respectively. Estimated NFV clearance was 3.18 L/h/kg. In conclusion, the population pharmacokinetic model describing the disposition of NFV and M8 should facilitate the design of future studies to elucidate the relative contributions of the parent compound and M8 to the pharmacological and toxic effects of NFV therapy. Clinical Pharmacology & Therapeutics (2004) 75, P15–P15; doi: