Pharmacokinetics and pharmacodynamics of intravenous ilaprazole in healthy subjects after single ascending doses

Abstract

1. Ilaprazole is a novel proton pump inhibitor and this is the first study to investigate the pharmacokinetics, pharmacodynamics and safety of intravenous ilaprazole in healthy volunteers. 2. In this open-label, single-dose, randomized and four-period crossover study, 16 healthy Chinese subjects received ilaprazole 5, 10 or 20 mg intravenously, or 10 mg orally. Serial blood and urine samples were collected and intragastric pH was recorded within 24 h. The percentage time of intragastric pH > 6 was the major index. Safety was assessed throughout the study. 3. Plasma exposure of intravenous ilaprazole increased proportionally over the dose of 5-20 mg. Clearance and volume of distribution were independent of dose. Ilaprazole was not eliminated through urine and the absolute bioavailability was 55.2%. For the intravenous dose of 5, 10, 20 mg, and oral dose of 10 mg, the mean percentages time of intragastric pH > 6 were 47.3%, 52.8%, 68.2% and 47.5%, respectively. 4. Ilaprazole showed linear pharmacokinetics over the dose of 5-20 mg. Intravenous ilaprazole provided rapid onset of action and the potency of effect were exhibited in a dose-dependent manner. Intravenous ilaprazole was safe and well tolerated except for elevated activated partial thromboplastin time (APTT) and prothrombin time (PT).

Efficacy, safety and pharmacokinetics of ilaprazole infusion in healthy subjects and patients with esomeprazole as positive control

“…Mean plasma concentration–time curves of infusions of ilaprazole and esomeprazole were shown in Figure and the PK parameters were shown in Table . In study A, the mean t 1/2 , CL and V of ilaprazole (30 mg) were 3.0 h, 3.1 L h −1 and 11.5 L h −1 , and these parameters were comparable to those from the previous study using 5, 10 and 20 mg . Dose‐proportionality over 5–30 mg was assessed using power model analysis.…”

“…Serial blood samples (3 mL) were collected for PK evaluation. In study A, the blood samples were drawn on day 1 at the following time points: 0 (predose), 15, 30, 45, 50 minutes, 1,2,3,4,5,8,12,16 and 24 hours. In study B, the blood samples were drawn on day 1 and 3 as follows: 0 (predose), 15, 30, 45, 50 minutes, 1, 2, 3, 4, 5, 8, 12, 16 and 24 hours, and were collected prior to dose (0 hours) and 45 minutes after dose on day 2.…”

“…Mean plasma concentration-time curves of infusions of ilaprazole and esomeprazole were shown in Figure 2 and the PK parameters were shown in Table 2. In study A, the mean t 1/2 , CL and V of ilaprazole (30 mg) were 3.0 h, 3.1 L h −1 and 11.5 L h −1 , and these parameters were comparable to those from the previous study using 5, 10 and 20 mg. 16 In study B, 12 healthy subjects received ilaprazole infusion 20 mg followed by 10 mg once daily for 2 days. After dose correction the accumulation index was 0.92 ± 0.10 based on AUC 0-t and 0.93 ± 0.06 based on C max , indicating that there was no accumulation after 3 days of multiple infusions.…”

“…The PK, PD and safety of ilaprazole infusion have been investigated in healthy subjects. It was reported that intravenous ilaprazole exhibited dose‐related effect of action and ilaprazole 20 mg provided the most significant pH control effect . However, there are problems remaining unsolved: (i) is 20 mg the right dose producing the best effect; (ii) is there a gap when extrapolating the PK and PD of ilaprazole from healthy subjects to patients; (iii) what is the optimum dose regimen for clinic?…”

“…It was reported that intravenous ilaprazole exhibited dose-related effect of action and ilaprazole 20 mg provided the most significant pH control effect. 16,17 However, there are problems remaining unsolved: (i) is 20 mg the right dose producing the best effect; (ii) is there a gap when extrapolating the PK and PD of ilaprazole from healthy subjects to patients; (iii) what is the optimum dose regimen for clinic? Therefore, the present study was designed to explore the potential PK and PD differences of ilaprazole infusion between healthy subjects and patients, to compare the efficacy of ilaprazole with esomeprazole in healthy subjects and patients with duodenal ulcers, and then determine the optimum dose regimen for Phase 2b/3 studies.…”