Variability in Systemic Pharmacokinetics of Amitriptyline by Blood pressure Alterations in Patients of Depression: A PD Based PK Analysis Model
Physiology of vascular system in designing therapeutics is yet in its infancy. Co–Morbid conditions like depression and hypertension are complex physiological and pathological situations where PBPK drug interactions are highly probable due to change in systemic blood pressure resulting in organ perfusion that is an important determinant of drug dispersion. To generate evidence in support of this probability, a single 100 mg dose of Amitriptyline an object drug was administered with 10 mg of Amlodipine as a precipitating drug in an open label, randomized parallel group, controlled clinical study based on PK/PD analysis model. Hypertensive patients with depression test group (TI), Hypertensive patients with out depression, test group (TII), Normotensive patients with depression, control group (CI) and Normal healthy volunteers, control group (CII), having 25 participants each were enrolled in this study. Plasma samples after single dose Amitriptyline at 0, 1, 2, 4, 8, 12, 24 hours were drawn along with measurement of heart rate, respiratory rate and blood pressure. A wash out period of 7 days for the two test groups (TI and TII) was given. Amlodipine 10 mg was administered which lowered the DBP by nearly 5 to 10 mm Hg, when the Amitriptyline was administered orally and the plasma samples were drawn for PK analysis along with PD parameters in a designed time event profile. Estimation of Amitriptyline and its metabolite Nortriptyline was performed by HPLC. Pharmacokinetic parameters were calculated using a non-compartmental model. After Amlodipine induced fall in DBP in both test groups, T1/2, C max, T max, CLT, AUC of Amitriptyline and Nortriptyline changed in both the test groups (TI and TII).