Validation study of a method for assaying DE-310, a macromolecular carrier conjugate containing an anti-tumor camptothecin derivative, and the free drug in human plasma by HPLC and LC/MS/MS.

DE-310 is a macromolecular carrier conjugate containing an anti-tumor camptothecin derivative, DX-8951, conjugated to a water-soluble polymer by means of a peptide spacer. New assay methods have been developed to determine the polymer-bonded DX-8951 conjugate, free DX-8951, and Glycyl-DX-8951 in human plasma. Solid-phase extraction was used to extract free DX-8951 and Glycyl-DX-8951 from plasma, and LC/MS/MS (Method I) was used to determine the amount of each analyte. Protein precipitation was used to extract Conjugated DX-8951, which was then digested with thermolysin. HPLC (Method II) was used to determine the productive compound (Phenylalanyl-Glycyl-DX-8951). The lower limit of quantitation of DX-8951 was 50 pg/ml, of Glycyl-DX-8951 was 80 pg/ml, and of Conjugated DX-8951 was 100 ng/ml (as DX-8951 equivalent). Both methods showed satisfactory sensitivity, precision, and accuracy.

Developmental pharmacokinetics and pharmacodynamics of nizatidine.

OBJECTIVES: To characterize the impact of development on the pharmacokinetics and pharmacodynamics of nizatidine. METHODS: Children (age range, 5 days-18 years) and adults (age range, 18-50 years) were enrolled in four open-label trials. Nizatidine formulation and dose were determined by age: infants received 2 or 4 mg/kg i.v., children 2.5 or 5 mg/kg in one of three oral liquid formulations, and adolescents and adults received a fixed 150-mg capsule. Nizatidine and N-desmethylnizatidine concentrations were measured in serial post-dose plasma samples by a high-performance liquid chromatographic assay with mass spectrometric detection. Intragastric pH was recorded during a 24-hour post-dose interval. RESULTS: Data on 93 subjects were combined with previous values from 36 individuals to cover an age group not adequately captured and to control for formulation effects. Dose-normalized exposure estimates revealed no apparent age dependence; however, maximum plasma concentration (298.5 +/- 100.7 v 552.8 +/- 152.4 ng/mL per mg/kg dose) and AUC0-infinity (954.4 +/- 379.8 v 1,573.0 +/- 347.4 ng*hour/mL per mg/kg dose) were reduced in extemporaneous formulations in apple juice. The apparent modest age dependence observed for total body clearance (Cl/F) (r = 0.365) and Vss/F (r = 0.221) reflected a formulation-dependent decrease in bioavailability rather than a true age effect. The age-associated changes in lambda z observed for nizatidine and its metabolite were predictable and consistent with developmental acquisition of renal function. Mean and median pH, as well as fraction of time that the dosing interval remained above target pH values, were significantly greater with administration of the drug than without. CONCLUSIONS: The biodisposition of nizatidine in children and adults is similar; however, response after a comparable weight-based dose is equal and potentially greater in children.

The bioequivalence of nizatidine (Axid) in two extemporaneously and one commercially prepared oral liquid formulations compared with capsule.

Nizatidine (Axid) is an H2-receptor antagonist used for the treatment of acid-related gastrointestinal disorders. Given the frequency of these conditions in children and the potential for pediatric use of nizatidine, an oral liquid dosage formulation would provide an alternative treatment option for patients unable to swallow solid oral dosage forms. This study was designed as an open-label, single-dose, four-way crossover trial to investigate the bioequivalence of 150 mg nizatidine administered in three oral liquid formulations (a commercially prepared oral syrup, an extemporaneous solution in apple juice, and an extemporaneous suspension in infant formula) relative to the marketed capsule formulation. Twenty-four adult subjects (ages 31.2 +/- 7.5 years; weight 71.1 +/- 11.8 kg) were enrolled, and blood samples for determination of plasma nizatidine concentrations were collected prior to drug administration and at 19 discrete intervals over a 24-hour postdose interval. Nizatidine was quantitated from plasma using a validated HPLC-MS assay, and a noncompartmental approach was used to describe nizatidine biodisposition in all subjects. Significant treatment effects were observed for log-normalized Cmax, AUC0-n, and AUC0-infinity (p < 0.001). Further evaluation revealed that nizatidine prepared in apple juice was markedly less bioavailable than the reference capsule, with 90% confidence intervals (CIs) of 0.518-0.626, 0.682-0.751, and 0.696-0.763 for Cmax, AUC0-n, and AUC0-infinity, respectively. The remaining two oral formulations demonstrated 90% CI within the guidelines established by the Food and Drug Administration (e.g., 0.80-1.25). Thus, nizatidine in infant formula and the commercially prepared oral syrup can be considered bioequivalent to the reference capsule.