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Nearly all international regimens for pediatric acute lymphoblastic leukemia (ALL) incorporate intravenous "high dose" methotrexate (HDMTX, ≥1 gram/m2 ) to penetrate the central nervous system. Dosing is routinely adjusted for body surface area (BSA) but limited data describe the pharmacokinetics of HDMTX, particularly in obese and/or large patients. To understand the impact of body size (BSA) and body fat percentage (BFP) on HDMTX pharmacokinetics, we performed a secondary analysis of 36 children and adolescents 10-21 years old treated for newly diagnosed ALL and who were enrolled in a prospective study examining body composition. All patients received 5 grams/m2 of HDMTX infused over 24 hours. Plasma methotrexate concentrations were measured at +24, +42, and +48 hours. At 48 hours, ≥0.4 μmol/L was defined as "delayed elimination" necessitating prolonged supportive care. BFP was measured using dual-energy x-ray absorptiometry. A nonparametric population pharmacokinetic model was constructed with subsequent simulations to explore effects of BSA and BFP extremes. Despite standard BSA-adjusted dosing, we found significant intra-patient variability in mean MTX concentration (38%, range 1.2-86%). BSA and BFP were not linearly associated with increased area under the curve (AUC, p = 0.74 and p = 0.12), but both larger size (BSA) and greater obesity (BFP) were associated with an approximately twofold higher risk for delayed elimination at 48 hours. HDMTX AUC was not associated with toxicity. MTX pharmacokinetics vary among and even within patients despite BSA-adjusted dosing. Obesity and large size are identified as new risk factors for delayed elimination requiring further investigation. This article is protected by copyright. All rights reserved.

Differences in physiology related to young or old age and/or organ system impairment alter the absorption, distribution, metabolism, and excretion of many medications and consequently their effectiveness and toxicity. This module discusses common alterations in medication use and dosage that are required in the pediatric age group, in the elderly, and in patients with renal or hepatic disease.

Few studies have characterized longitudinal female plasma and genital antiretroviral pharmacokinetics and pharmacodynamics. Among 20 regimen-naive HIV-infected adult women initiating atazanavir-based therapy (n = 9) or efavirenz-based therapy (n = 11), we measured blood CD4+ T lymphocytes, and paired plasma and genital HIV RNA and atazanavir or efavirenz 2 days before starting therapy and 2, 4, 7, 10, 21, 28, 60, 120, and 180 days after. The mean (range) log10 baseline plasma viral load was 4.89 copies/mL (2.64-6.09 copies/mL), and genital was3.30 (1.60-5.00). In the atazanavir and efavirenz groups, mean (SD) days to a 50% decrease in plasma viral load was 8.2 (4.9) versus 9.3 (7.4), P = .7, and in the genital tract it was 7.3 (3.5) versus 9.3 (7.7), P = .5. The median (interquartile range) plasma:genital concentration ratio for atazanavir was 0.11 (0.001-0.46) versus 0.34 (0.05-1.30) for efavirenz, P = .5. Average plasma efavirenz or atazanavir concentrations over time did not affect virologic response. Blood CD4+ percentages increased by +2.3 (P = .06) and +3.0 (P = .003) for every 1 mg/L increase in average plasma and genital drug concentration, respectively. Plasma and genital viral pharmacodynamics were similar between the groups and independent of average concentrations, but blood CD4+ response was related in particular to genital extravascular drug concentrations.

Individualized, model-based, target-oriented optimal concentration-controlled dosing of HIV medications can be beneficial to patients for whom there are limited dosing guidelines, such as children, adolescents, or patients with altered physiologic function. Barriers to this approach include lack of training, expertise, and access to appropriate software to assist the clinician. The authors present 4 illustrative clinical cases of HIV-infected patients whose therapy was optimized using population pharmacokinetic models (here generated from published studies) and supplemented by individualized Bayesian adaptive control of dosage regimens as implemented in the MM-USCPACK software. These 4 cases illustrate how clinicians can maximize therapeutic success in (1) patients with reduced drug clearance, (2) young adolescents transitioning to adult physiology, (3) patients with dose-dependent toxicity, and (4) adolescents with limited therapeutic options.