Effect of Body Fat on Population Pharmacokinetics of High-Dose Methotrexate in Pediatric Patients With Acute Lymphoblastic Leukemia.

Nearly all international regimens for pediatric acute lymphoblastic leukemia (ALL) incorporate intravenous "high-dose" methotrexate (HDMTX, ≥1 g/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 g/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 intrapatient 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 2-fold 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.

Spray-dried high-amylose sodium carboxymethyl starch: impact of α-amylase on drug-release profile.

Spray-dried high-amylose sodium carboxymethyl starch (SD HASCA) is a promising pharmaceutical excipient for sustained-release (SR) matrix tablets produced by direct compression. The presence of α-amylase in the gastrointestinal tract and the variations of the gastric residence time of non-disintegrating dosage forms may affect the presystemic metabolism of this excipient and, consequently, the drug-release profile from formulations produced with SD HASCA. In this study, the influence of α-amylase and the residence time in acidic conditions on the drug-release profile was evaluated for a once-daily acetaminophen formulation (Acetaminophen SR) and a once-daily tramadol hydrochloride formulation (Tramadol SR). Both formulations were based on SD HASCA. α-Amylase concentrations ranging from 0 IU/L to 20000 IU/L did not significantly affect the drug-release profiles of acetaminophen and tramadol hydrochloride from SD HASCA tablets (f2 > 50) for all but only one of the studied conditions (f2 = 47). Moreover, the drug-release properties from both SD HASCA formulations were not significantly different when the residence time in acidic medium was 1 h or 3 h. An increase in α-amylase concentration led to an increase in the importance of polymer erosion as the main mechanism of drug-release instead of drug diffusion, for both formulations and both residence times, even if release profiles remained comparable. As such, it is expected that α-amylase concentration and residence time in the stomach will not clinically affect the performance of both SD HASCA SR formulations, even if the mechanism of release itself may be affected.

High-amylose sodium carboxymethyl starch matrices: development and characterization of tramadol hydrochloride sustained-release tablets for oral administration.

Substituted amylose (SA) polymers were produced from high-amylose corn starch by etherification of its hydroxyl groups with chloroacetate. Amorphous high-amylose sodium carboxymethyl starch (HASCA), the resulting SA polymer, was spray-dried to obtain an excipient (SD HASCA) with optimal binding and sustained-release (SR) properties. Tablets containing different percentages of SD HASCA and tramadol hydrochloride were produced by direct compression and evaluated for dissolution. Once-daily and twice-daily SD HASCA tablets containing two common dosages of tramadol hydrochloride (100 mg and 200 mg), a freely water-soluble drug, were successfully developed. These SR formulations presented high crushing forces, which facilitate further tablet processing and handling. When exposed to both a pH gradient simulating the pH variations through the gastrointestinal tract and a 40% ethanol medium, a very rigid gel formed progressively at the surface of the tablets providing controlled drug-release properties. These properties indicated that SD HASCA was a promising and robust excipient for oral, sustained drug-release, which may possibly minimize the likelihood of dose dumping and consequent adverse effects, even in the case of coadministration with alcohol.