Assessment of the trial drugs ACH-0143102 and ACH-0142684, when taken by healthy men and women.
A Phase 1, Double Blind, Randomized, Placebo Controlled, Parallel Design Pharmacokinetic Drug Interaction Study of ACH-0143102 and ACH-0142684 in Healthy Volunteers.
Achillion Pharmaceuticals, Inc
36 participants
Feb 3, 2014
Interventional
Conditions
Summary
This is a Phase 1 study designed to assess the pharmacokinetics and safety of ACH-0143102 in combination with ACH-0142684 when administered to healthy volunteers. In each of 2 groups, a monotherapy phase of each drug will precede the addition of the second drug. The duration of each monotherapy arm is designed to ensure that steady state conditions are achieved before the second drug is added. Given the observed half life and associated variability for ACH-0142684 200mg, the 7 day duration of monotherapy in Group 1 ensures that steady state conditions are achieved prior to initiation of ACH-0143102. The plasma terminal half life of ACH-0143102 is considerably longer, approximately 250 hours, and the duration of the monotherapy phase in Group 2 is therefore increased to 14 days in order to achieve near steady state conditions. In this study, a full PK profile (0-24 hr) is obtained for each drug when administered alone at steady state (last day of monotherapy phase), after one dose of the other drug when the other drug is at steady state (first day of co-administration period), and after both drugs have achieved steady state conditions (last day of co-administration period). The use of a fairly large control group (active:control = 2:1) will decrease the likelihood that random safety events are erroneously attributed to the study drug. In order to obtain the intensive pharmacokinetic evaluations needed and optimally manage subject safety, all subjects will remain in house during the entire study. Safety evaluations will be performed on subjects daily, and safety laboratory assessments will be reviewed in real time to facilitate early intervention for any safety issues identified during the study. Assuming that data from this study demonstrate no insurmountable pharmacokinetic issues, and that no important safety issues are identified, the results of this Phase 1 study will be used to support initiation of a proof of concept study with HCV patients.
Eligibility
Inclusion Criteria13
- Healthy, adult, male or female subjects, 18 to 55 years of age, inclusive.
- Continuous non smokers who have not used nicotine containing products for at least 3 months prior to the first dose.
- Weigh at least 50kg and have a Body Mass Index (BMI) in the range 18 to 30.
- Medically healthy with no clinically significant laboratory profiles, vital signs or ECGs; as assessed by the PI.
- Liver function tests (serum alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase [ALP]) and serum bilirubin (total and direct) must be below or equal to the upper limit of normal (ULN) at screening.
- Females must be of non childbearing potential, defined as having undergone one of the following sterilization procedures at least 6 months prior to Day 1:
- hysterectomy;
- bilateral oophorectomy
- bilateral tubal ligation or fallopian tube inserts or be postmenopausal with amenorrhea for at least 1 year prior to Day 1 and have follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status.
- Males must use a condom with spermicide when engaged in sexual activity from first check in through 90 days beyond the last dose.
- Males must agree to refrain from sperm donation from first check in through 90 days beyond the last dose.
- Give voluntary written informed consent to participate in the study.
- Able to effectively communicate with the Investigator and other center personnel, and willing to comply with all study requirements and restrictions.
Exclusion Criteria21
- History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease in the opinion of the PI.
- History or presence of alcoholism and/or drug abuse within the past 2 years.
- History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds.
- History or presence of diabetes mellitus or hyperglycemia, in the opinion of the PI.
- Female subjects who are pregnant or lactating.
- Have positive results for the urine drug screen at screening or check in.
- Have positive urine cotinine at screening.
- Have positive results at screening for HIV, HBsAg or HCV.
- Seated sustained blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
- Heart rate is lower than 40 bpm or higher than 99 bpm at screening.
- lead ECGs which have clinically significant findings as judged by the PI or the PI’s designee at screening and prior to dosing, including:
- QTcB interval is >450 msec;
- PR interval > 200 msec.
- QRS interval > 120 msec.
- Has an estimated creatinine clearance < 90 mL/min based on the Cockcroft Gault equation at the screening visit.
- Have used any drugs or substances known to be significant inhibitors of CYP enzymes and/or significant inhibitors or substrates of P gp and/or OATP within 14 days prior to the assigned first dose of study drug.
- Have used any drugs or substances known to be significant inducers of CYP enzymes and/or P gp within 28 days prior to the assigned first dose of study drug.
- Have been on a special diet within the previous 28 days which, in the opinion of the investigator, would interfere with subject safety or compliance with the protocol.
- Have a hemoglobin level below the lower limit of normal at screening and first check in.
- Have made a donation of blood or had significant blood loss within 56 days prior to the assigned first dose of study drug.
- Have participated in another clinical trial within 28 days prior to the assigned first dose of study drug.
Interventions
Adminstration of ACH-0142684 at 200mg per day and ACH-0143102 at 25mg per day together. Group 1 subjects will receive 21 days of ACH-0142684 and 14 days of ACH-0143102 (introduced at Day 8). Group 2 subjects will receive 21 days of ACH-0143102 and 7 days of ACH-0142684 (introduced at Day 15). ACH-0142684 will be a 2ml solution administered orally via a syringe. ACH-0143102 will be a single capsule administered orally. Medication compliance and adherence will be monitored by weighing, counting and calculating both of the remaining product and monitoring the source documentation regarding drug administration. All drug will be taken in clinic under staff supervision and recorded in the subject notes / source documentation.
Locations(1)
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ACTRN12614000102673