ABSTRACT
The aim was to assess the bioequivalence of Sandoz methylphenidate osmotic-controlled release (OCR) tablets (Sandoz [Methylphenidate[ MPH OCR) with Concerta®, a methylphenidate formulation indicated for the treatment of attention deficit/hyperactivity disorder (ADHD). Four open-label, randomized, single-dose, two-way crossover bioequivalence studies were conducted in healthy subjects: three fasting studies with 54-, 36- and 18-mg doses of methylphenidate, and one fed study with the 54-mg dose. The d- and l-threo-methylphenidate plasma levels were quantified using liquid chromatographic methods with tandem mass spectrometry (LC MS/MS). Bioequivalence of the formulations was accepted if the 90% geometric confidence intervals of the ratio of least-squares means of Sandoz MPH OCR to Concerta® of ln-transformed area under the curve (AUC0-t ) and C max were within the acceptance range of 80-125%. All studies met the bioequivalence criteria, and 90% geometric confidence intervals for AUC0-t and C max were within the predefined range. All plasma concentration time curves for Sandoz MPH OCR under fasting conditions showed a biphasic profile comparable with Concerta®, confirmed by bioequivalence of the partial metrics AUC0-2h, AUC2-24 h, C max(0-2 h) and C max(2-24 h). Both products were well tolerated and no relevant differences in the safety profiles were observed. It was concluded that Sandoz MPH OCR is bioequivalent to Concerta® in terms of rate and extent of absorption when administered as a single dose of one extended-release tablet of 54, 36, or 18 mg under fasting conditions and at a dose of 54 mg under fed conditions.
ABSTRACT
Cross signal contributions between an analyte and its internal standard (IS) are very common due to impurities in reference standards and/or isotopic interferences. Despite the general awareness of this issue, how exactly they affect quantitation in LC-MS based bioanalysis has not been systematically evaluated. In this research, such evaluations were performed first by simulations and then by experiments using a typical bioanalytical method for tiagabine over the concentration range of 1-1000 ng/mL in human EDTA K(3) plasma. The results demonstrate that when an analyte contributes to IS signal, linearity and accuracy can be affected with low IS concentration. Thus, minimum IS concentrations have been obtained for different combinations of concentration range, percentage of cross contribution, and weighting factor. Moreover, while impurity in analyte reference standard is a factor in cross signal contribution, significant systematic errors could exist in the results of unknown samples even though the results of calibration standards and quality controls are acceptable. How these systematic errors would affect stability evaluation, method transfer, and cross validation has also been discussed and measures to reduce their impact are proposed. On the other hand, the signal contribution from an IS to the analyte causes shifting of a calibration curve, i.e. increase of intercept, and theoretically, the accuracy is not affected. The simulation results are well supported by experimental results. For example, good inter-run (between-run) accuracy (bias: -2.70 to 5.35%) and precision (CV: 2.07-10.50%) were obtained when runs were extracted with an IS solution containing 1-fold of the lower limit of quantitation.
