Subjects
Male volunteers between 18 to 65 years of age and an BMI between 18 and 30 kg/m2, determined to be healthy based on a full medical screening, were included in a first-in-human double-blind, randomized, placebo controlled, cross-over SAD (N=23) and MAD study (N=30) conducted at the Centre for Human Drug Research in Leiden, The Netherlands. Subjects were not allowed to use any medication (except for occasional use of paracetamol or non-steroidal topical medication). Subjects fasted from 10 hours before until 4 hours after each dose administration. Three subjects participated in a preceding exploratory study that guided blood sampling schemes for subsequent SAD cohorts. Furthermore, healthy males were enrolled in an additional food effect cohort (N=6). In addition, a group of healthy postmenopausal females (N=8) between 45 to 65 years of age and a body mass index between 18 and 30 kg/m2 was included to evaluate potential gender differences in drug effect. All volunteers provided written informed consent before study participation. The studies were approved by the Medical Ethics Review Committee of Leiden University Medical Center (EudraCT number 2007-001993-10) and carried out in accordance with the Declaration of Helsinki. Figure 2 provides a schematic overview of the study design.
Study design and treatmentSingle ascending dosing
In the SAD study, 23 healthy males received an oral dose administration of Org 48775-0 in a double-blind, randomized, placebo controlled, cross-over fashion. Org 48775-0 was administered orally as a solution in 2x100 mL of orange juice under fasting conditions. Prior to the study, an exploratory study was performed wherein 0.15 mg Org 48775-0 and 0.30 mg Org 48775-0 was administered to 2 volunteers and 1 volunteer respectively, to account for large inter-species differences observed in preclinical pharmacokinetic studies. Using the obtained pharmacokinetic data from this exploratory study, a starting dose of 0.3 mg Org 48775-0 for the SAD study part was determined, followed by 9 consecutive dose levels of Org 48775-0. Subjects were treated with placebo and maximally 3 ascending doses of Org 48775-0. Each dose was administered 2 weeks after the previous dose to ensure a wash-out period of at least five times t1/2. The follow-up visit took place approximately 14 days after administration of the last dose. After each dose administration pharmacokinetic, pharmacodynamic (inhibition of LPS-induced TNFα release), and routine clinical and laboratory data were evaluated and a decision was made on further dose escalation.
Evaluation of food effectThe effect of a standardized fat meal opposed to no meal (fasting state) was evaluated in 6 healthy male volunteers who received 100 mg Org 48775-0 in the SAD study. In one occasion, 100 mg Org 48775-0 was administered orally as a suspension in 2x100 mL of orange juice under fasting conditions and in the second occasion (two weeks later), the drug was administered 30 minutes after intake of the standardized meal. The energy content in one standardized fat meal was estimated to be 185 kcal protein, 284 kcal carbohydrates and 482 kcal lipids, which is in accordance with FDA guidelines for food interaction studies (Guidance for Industry; food effect bioavailability and fed bioequivalence studies; 150 kcal protein, 250 kcal carbohydrates, and 500-600 kcal fat). During the second occasion, the subjects started fasting 10 hours prior to drug administration until 4 hours after dosing. The clock-time of drug administration and study-related assessments was comparable for both occasions.
Evaluation of gender differences Potential gender differences in PK and PD characteristics of Org 48775-0 were evaluated after administration of a single dose of 100 mg, in 8 healthy postmenopausal females and 11 healthy males taking part in the SAD study.