Effect of verapamil on the pharmacokinetics of pasireotide in healthy volunteers

Abstract

We evaluated the drug-drug interaction between pasireotide SC and verapamil, a known P-glycoprotein inhibitor. Subjects received pasireotide SC (single dose, 600 mg) on day 1, and samples for pharmacokinetics evaluation were collected from days 1 to 8. Subjects received an oral dose of verapamil 240 mg/d for 10 days (days 15-24). On day 18, subjects also received pasireotide SC 600 mg. Pharmacokinetic sampling for pasireotide SC and verapamil was done during days 18 to 25 and days 15 to 21, respectively. Safety evaluations were performed throughout the study period, including a 30-day post-treatment follow-up. Pharmacokinetic profiles of pasireotide SC alone and in combination with verapamil sustained-release (SR) were superimposable with the geometric mean ratios (90% confidence interval [CI]) of 0.98 (0.91-1.06) for C max , 0.97 (0.90-1.04) for AUC last , and 0.98 (0.92-1.05) for AUC inf . Exploratory analyses showed a 17% (90% CI, 0.72-0.94) reduction in C trough and 31% (0.58-0.82) reduction in C max (8 hours post-dose) for verapamil SR with pasireotide SC versus verapamil alone. Pasireotide SC with or without verapamil was well tolerated. In conclusion, there was no change in the rate of pasireotide absorption and elimination or extent of exposure following concomitant administration with verapamil. Keywords drug-drug interaction, pasireotide, P-gp inhibitor, verapamil, pharmacokineticsPasireotide (SOM230), a second-generation, multireceptortargeted somatostatin analogue (SSA), exhibits a unique binding profile with higher binding affinity to four of the five known human somatostatin receptor subtypessst 1,2,3 and sst 5 .1,2 Due to its unique binding profile, pasireotide has shown promising results in patients with gastroenteropancreatic neuroendocrine tumors, acromegaly, and Cushing's disease. [3][4][5][6][7] The pasireotide subcutaneous (SC) formulation is indicated in patients with Cushing's disease for whom pituitary surgery is not an option or surgery has not been curative, 8 and as of December 2013, it has been approved in 50 countries.In patients with Cushing's disease and acromegaly, pasireotide SC demonstrates a dose-proportional and time-independent pharmacokinetic (PK) profile at a dose range of 300 to 1200 mg. 5,[8][9][10][11] Pasireotide SC has shown a linear PK with acceptable safety and tolerability within a dose range from 2.5 to 1500 mg in healthy volunteers. 8 The PK profile of pasireotide SC in healthy volunteers exhibits rapid absorption (T max , 0.25-0.5 h), low clearance (CL/F,~8-9 L/h), large volume of distribution (V z /F >100 L), and effective half-life (T 1/2 eff ,~12 hours, based on area under curve [AUC] accumulation ratio with once-daily dosing for 14 days) with favorable tolerability in a single-or multiple-dose regimen. [8][9][10]12 Results from human PK studies indicate that pasireotide, when administered subcutaneously, is mainly eliminated via the liver with a minimal renal contribution. 13 Pasireotide has low passive permeability and is likely to be a substrate of ...

Downregulation of MACC1 facilitates the reversal effect of verapamil on the chemoresistance to active metabolite of irinotecan in human colon cancer cells

“…VER resists MDR in tumors by regulating the expression of P-gp. It can inhibit or downregulate the expression of P-gp, prevent the discharge of drugs, and improve the killing effect of chemotherapeutics on tumors ( Kornberger et al., 2014 ; L. Wang and Sun, 2020 ). However, the effective and ineffective targets of the antagonizing drug-resistance therapy of VER and related action mechanisms remain unclear.…”