Bioequivalence Study Of Pramipexole Dyhydrochloride Monohydrate 0.18 MG Tablet Versus 'Sifrol' 0.18 MG Tablets in Healthy Adult Subjects Under Fasting Conditions: A Randomized, Open-Label, Two-way Crossover Study

Abstract

Looking at the spread of Parkinson’s disease worldwide, there is need to develop and make available the maximum generic medicines at low cost, for the treatment of Parkinson’s disease. Bioavailability is the rate and extent of drug reaching in the systemic circulation after administration with the stated route. Comparison of bioavailability of various formulations with each other is called as Bioequivalence (BE). Bioequivalence studies are required for pharmaceutical industry to meet the regulatory requirements in launching the generic Products in market. The brand name is the name under which a new innovator medication is developed and marketed. When a pharmaceutical company develops a new medication, they obtain patent for it. Brands are usually given patent protection for about 20 years. When the patent of a brand name drug expires, other companies can introduce its generic version. Pramipexole is considered a non-ergot dopamine that has higher binding affinity to D3 receptor and shows higher intrinsic activity via D2 receptor. Thus pramipexole is selective towards dopamine receptor rather than other receptors, preferred for the treatment of Parkinson’s disease. An open label, balanced, randomized, two-treatment, two-sequence, two-period, crossover, single-dose comparative oral bioavailability study of Pramipexole dihydrochloride monohydrate 0.18 mg tablets and ‘SIFROL® ’ 0.18 mg tablets in healthy adult human subjects under fasting conditions performed as recommended by regulatory authority. 40 healthy volunteers were assigned for the study between 18 and 45 years, Screened within 21 days prior to administration of first dose of study drug. One tablet of either the test product Pramipexole dihydrochloride monohydrate 0.18 mg tablets or reference product ‘SIFROL® ’ 0.18 mg tablets was administered at ‘0.0 hour’ to the subjects in a sitting posture with 240 mL of water at ambient temperature in each period. All subjects were housed in the clinic from at least 11 hours before dosing to at least 24 hours post dose. Subjects were reported to the clinic for 36.0, 48.0 & 60.0 hours post dose ambulatory blood samples collection. Pharmacokinetic parameters Cmax, AUCt, AUCi, Tmax, Kel and t1/2 will be calculated using WinNonlin® professional software. Statistical analysis will be performed on the pharmacokinetic parameters by using SAS® statistical software. ABSTRACT 2021 Department of Pharmaceutical Sciences and Technology, MRSPTU Page vi Total 31 (Subject no 01, 03-07, 09-23, 25-28, and 30-35) subjects completed the study. After applying the Lund's outlier test, subject#34 was detected as an outlier in pramipexole data, but looking at the time-concentration profile and clinical data (no adverse event reported), subject#34 cannot be treated as clinical outlier. So statistical analysis was performed on all the subjects who completed the study. The analysis of the plasma pramipexole data resulted in no statistically significant, a = 0.05, differences between product and dosing period for logtransformed AUCt, AUCi and Cmax. The analysis of the plasma pramipexole data resulted in no statistically significant, a = 0.05, differences between dosing sequence for log-transformed AUCt and AUCi. The analysis of the plasma pramipexole data resulted in statistically significant, a= 0.05, differences between dosing sequence for log-transformed Cmax. The differences between the LSMEAN Test values and the corresponding LSMEAN Reference values of plasma pramipexole relative to reference LSMEAN are -3.5% for Tmax, 0.0% for Kel and 1.7% for tHalf. The differences between the GEOMEAN Test values and the corresponding GEOMEAN Reference values of plasma pramipexole relative to reference GEOMEAN are 0.7% for Cmax, 1.5% for AUCt and 1.9% for AUCi. For the log transformed Pramipexole data, the 90% confidence intervals about the ratio of the Test geometric mean to Reference geometric mean are within the 80% to 125% limits for AUCt, AUCi and Cmax. The geometric mean of the test and reference ratios were 101.02% (90% CI, 98.95 - 103.12) and 98.22% (90% CI, 96.22 - 100.27) and 98.22% (90% CI, 96.22 - 100.27) respectively, for Cmax, AUCt and AUCinf respectively. There were no severe adverse events or other adverse events with clinical significance during the study. In these healthy subjects, the results showed that test and reference drug formulations were bioequivalent