This study is an open-label, prospective pharmacokinetic study investigating two antiretroviral agents in parallel and employing an adaptive design with two stages, whereby the results obtained in the primary stage inform the doses selected for investigation in the secondary stage
The objectives of this study are: Primary * To investigate the pharmacokinetics of a new pharmaceutical formulation of efavirenz (NANO-efavirenz) in HIV negative healthy volunteers after single dose and a steady-state. * To investigate the pharmacokinetics of a new pharmaceutical formulation of lopinavir (NANO-lopinavir) in HIV negative healthy volunteers Secondary * To investigate the safety and tolerability of NANO-efavirenz and NANO-lopinavir in HIV negative healthy volunteers * To assess the bioequivalence of a selected single-dose of NANO-efavirenz to a single dose 600mg of efavirenz as Sustiva® * To investigate the association between genetic polymorphisms in drug disposition genes and drug exposure
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
50
St Stephen's Centre
London, London, United Kingdom
The pharmacokinetics of a new pharmaceutical formulation of efavirenz (NANOefavirenz) and lopinavir (NANOlopinavir) in HIV negative healthy volunteers, as measured by Ctrough
Trough concentration (Ctrough) is defined as the concentration at 24 hours after the observed drug dose.
Time frame: Assessed from baseline visit (day 1) to : 1) Day 31 (Primary Stage Group A); 2) Day 30 (Primary Stage Group B); 3) Day 80 (Secondary Stage Group A); 4) Day 30 (Secondary Stage Group B)
The pharmacokinetics of a new pharmaceutical formulation of efavirenz (NANOefavirenz) and lopinavir (NANOlopinavir) in HIV negative healthy volunteers, as measured by Cmax
Cmax is defined as the maximum observed plasma concentration
Time frame: Assessed from baseline visit (day 1) to : 1) Day 31 (Primary Stage Group A); 2) Day 30 (Primary Stage Group B); 3) Day 80 (Secondary Stage Group A); 4) Day 30 (Secondary Stage Group B)
The pharmacokinetics of a new pharmaceutical formulation of efavirenz (NANOefavirenz) and lopinavir (NANOlopinavir) in HIV negative healthy volunteers, as measured by t1/2
t1/2 is defined as the elimination half-life
Time frame: Assessed from baseline visit (day 1) to : 1) Day 31 (Primary Stage Group A); 2) Day 30 (Primary Stage Group B); 3) Day 80 (Secondary Stage Group A); 4) Day 30 (Secondary Stage Group B)
The pharmacokinetics of a new pharmaceutical formulation of efavirenz (NANOefavirenz) and lopinavir (NANOlopinavir) in HIV negative healthy volunteers, as measured by Tmax
Tmax is defined as the time point at Cmax (Tmax)
Time frame: Assessed from baseline visit (day 1) to : 1) Day 31 (Primary Stage Group A); 2) Day 30 (Primary Stage Group B); 3) Day 80 (Secondary Stage Group A); 4) Day 30 (Secondary Stage Group B)
The pharmacokinetics of a new pharmaceutical formulation of efavirenz (NANOefavirenz) and lopinavir (NANOlopinavir) in HIV negative healthy volunteers, as measured by total drug exposure
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BID
OD
OD
OD
BID
BID
Total drug exposure will be expressed as the area under the plasma concentration-time curve (AUC): from 0-12 (AUC0-12h) and 0-56 hours (AUC0-56h) for lopinavir; or 0-24 (AUC0-24h) and 0-228 hours (AUC0-24h) for efavirenz.
Time frame: Assessed from baseline visit (day 1) to : 1) Day 31 (Primary Stage Group A); 2) Day 30 (Primary Stage Group B); 3) Day 80 (Secondary Stage Group A); 4) Day 30 (Secondary Stage Group B)
Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by concomitant medication check
Time frame: 1) From screening visit to day 45 (Primary Stage Group A); 2) From screening visit to day 44 (Primary Stage Group B); 3) From screening visit to day 94 (Secondary Stage Group A); 4) From screening visit to day 44 (Secondary Stage Group B)
Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by Adverse Events
Time frame: 1) From screening visit to day 45 (Primary Stage Group A); 2) From screening visit to day 44 (Primary Stage Group B); 3) From screening visit to day 94 (Secondary Stage Group A); 4) From screening visit to day 44 (Secondary Stage Group B)
Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by symptom directed physical exam
Time frame: 1) From screening visit to day 45 (Primary Stage Group A); 2) From screening visit to day 44 (Primary Stage Group B); 3) From screening visit to day 94 (Secondary Stage Group A); 4) From screening visit to day 44 (Secondary Stage Group B)
Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by vital signs
Temperature, blood pressure, heart rate, and respiratory rate
Time frame: 1) From screening visit to day 45 (Primary Stage Group A); 2) From screening visit to day 44 (Primary Stage Group B); 3) From screening visit to day 94 (Secondary Stage Group A); 4) From screening visit to day 44 (Secondary Stage Group B)
Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by ECG
12 lead ECG with calculation of corrected QT interval (Fredericia)
Time frame: 1) From screening visit to day 21 (Primary Stage Group A); 2) From screening visit to day 28 (Primary Stage Group B); 3) From screening visit to day 70 (Secondary Stage Group A); 4) From screening visit to day 28 (Secondary Stage Group B)
Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by Urinalysis
Glucose, ketones, blood, pH, proteins, nitrites and leucocytes Pregnancy test for females of childbearing potential (urine) Drug screen
Time frame: ) From screening visit to day 21 (Primary Stage Group A); 2) From screening visit to day 28 (Primary Stage Group B); 3) From screening visit to day 70 (Secondary Stage Group A); 4) From screening visit to day 28 (Secondary Stage Group B)
Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured haematology
1. Coulter count with differential 2. Clotting screen; PT, APTT, Fibrinogen
Time frame: 1) From screening visit to day 45 (Primary Stage Group A); 2) From screening visit to day 44 (Primary Stage Group B); 3) From screening visit to day 94 (Secondary Stage Group A); 4) From screening visit to day 44 (Secondary Stage Group B)
Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by clinical chemistry
Serum Biochemistry - Including sodium, potassium, urea, creatinine, total cholesterol and triglycerides, calcium, phosphate, liver enzymes (ALT, AST, GGT), albumin, glucose.
Time frame: 1) From screening visit to day 45 (Primary Stage Group A); 2) From screening visit to day 44 (Primary Stage Group B); 3) From screening visit to day 94 (Secondary Stage Group A); 4) From screening visit to day 44 (Secondary Stage Group B)
Safety and tolerability of NANOefavirenz and NANOlopinavir in HIV negative healthy volunteers, as measured by Adherence questioning/ pill count
Time frame: 1) Days 14 and 21 (Primary Stage Group A); 2) Days 7 and 28 (Primary Stage Group B); 3) Days 14, 21, 63, and 70 (Secondary Stage Group A); 4) Days 7 and 28 (Secondary Stage Group B)
Safety and tolerability of NANOefavirenz in HIV negative healthy volunteers, as measured by CNS symptoms questionnaire
Time frame: 1) Days 2 and 21 (Primary Stage Group A); 2) Days 2, 21, 51, and 70 (Secondary Stage Group A)
Relationship between genetic polymorphisms and exposure to the studied drugs.
Preliminary comparison between genotype and phenotype
Time frame: Sample taken at baseline (if consented)