Pharmacokinetic Study of the HCV Protease Inhibitor Boceprevir and the HIV Integrase Inhibitor Raltegravir (OPAL)

Study Description

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Brief Summary:

The objective of this study is to evaluate the effect of boceprevir (steady state) on the pharmacokinetics of a single dose of raltegravir. The effect on the boceprevir pharmacokinetics of a single dose raltegravir will also be evaluated (compared to historical controls). Furthermore, the safety profile of the combination is studied.

Condition or disease	Intervention/treatment	Phase
HIV Infections; HCV Infections	Drug: boceprevir; Drug: raltegravir	Phase 1

Detailed Description:

A considerable percentage of HIV infected patients is also infected with the hepatitis C virus (HCV). HIV/HCV co-infected patients are likely to simultaneously use treatment for their HIV infection as well as HCV treatment. Therefore, it is important to know if drug-drug interactions occur when combining those treatments.

Raltegravir is an HIV integrase inhibitor and approved by the FDA in 2007. Boceprevir is a potent HCV NS3 serine protease inhibitor and is currently in Phase III clinical development.

Combined use of boceprevir and raltegravir is not expected to give a major drug-drug interaction as raltegravir is not a CYP3A substrate and thus will not be affected by the strong inhibition of CYP3A by boceprevir. Raltegravir is metabolized by UGT but boceprevir is not known to influence UGT. However, recent data indicate that raltegravir is a P-gp substrate and boceprevir is a substrate and a moderate inhibitor of P-gp in vitro.

Even when no drug interaction is expected, it may be recommended to collect sufficient evidence that this is the case as in many cases un-expected drug-drug interactions have been observed in the past.

The current study is designed to evaluate the effect of steady state boceprevir on the pharmacokinetics of a single dose of raltegravir and the safety profile when used in combination. Furthermore the effect of a single dose raltegravir is studied on the pharmacokinetics of steady state boceprevir in comparison with historical controls.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	24 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Pharmacokinetic Study of the HCV Protease Inhibitor Boceprevir and the HIV Integrase Inhibitor Raltegravir
Study Start Date :	August 2011
Actual Primary Completion Date :	November 2011
Actual Study Completion Date :	December 2011

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Experimental: boceprevir + raltegravir; 9 days of boceprevir 800mg TID; day 10 two doses of boceprevir 800mg and one dose of raltegravir 400mg	Drug: boceprevir; 10 days of boceprevir 800mg TID Drug: raltegravir; raltegravir 400mg single dose; Other Name: Isentress
Active Comparator: raltegravir alone; single dose of raltegravir 400mg	Drug: raltegravir; raltegravir 400mg single dose; Other Name: Isentress

Outcome Measures

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Primary Outcome Measures :

1. raltegravir concentrations [ Time Frame: during 12hours on two occasions ]
   To determine the effect of chronic use of boceprevir on the single-dose pharmacokinetics of raltegravir 400mg in healthy volunteers

Secondary Outcome Measures :

1. adverse events [ Time Frame: entire study ]
   to determine the safety of a single dose of raltegravir 400mg when combined with chronic use of boceprevir
2. boceprevir concentrations [ Time Frame: during 8 hours on one occasion; predose 4 times over a period of 10 days ]
   To determine the effect of a single-dose pharmacokinetics of raltegravir 400mg on chronic use of boceprevir in healthy volunteers

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 55 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

• Subject is at least 18 and not older than 55 years at scree-ning.
• Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to the first dosing
• Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included.
• Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.
• Subject is in good age-appropriate health condition as established by medical history, physical examination, electrocardiography, results of biochemistry, haematology and urinalysis testing within 4 weeks prior to Day 1. Results of biochemistry, haematology and urinalysis testing should be within the laboratory's reference ranges. If laboratory results are not within the reference ranges, the subject is included on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded.
• Subject has a normal blood pressure and pulse rate, according to the Investigator's judgement.

Exclusion Criteria:

• Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.
• Positive HIV test.
• Positive hepatitis B or C test.
• Pregnant female (as confirmed by an HCG test performed less than 4 weeks before Day 1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the entire conduct of the trial.
• Therapy with any drug (for two weeks preceding dosing), ex-cept for paracetamol.
• Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), psychiatric disorders, gastro-intestinal disorders, renal and hepatic disorders, hormonal disorders (especially diabetes mellitus), coagulation disorders.
• Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion.
• History of or current abuse of drugs, alcohol or solvents.
• Inability to understand the nature and extent of the trial and the procedures required.
• Participation in a drug trial within 60 days prior to the first dose.
• Donation of blood within 60 days prior to the first dose.
• Febrile illness within 3 days before the first dose.

Contacts and Locations

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Locations

Netherlands
CRCN
Nijmegen, Netherlands

Sponsors and Collaborators

Radboud University

Merck Sharp & Dohme Corp.

Investigators

Principal Investigator:	David Burger, PharmD, PhD	Radboud University

More Information

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Additional Information:

abstract with results of the study, presented at CROI 2012 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

de Kanter CT, Blonk MI, Colbers AP, Schouwenberg BJ, Burger DM. Lack of a clinically significant drug-drug interaction in healthy volunteers between the hepatitis C virus protease inhibitor boceprevir and the HIV integrase inhibitor raltegravir. Clin Infect Dis. 2013 Jan;56(2):300-6. doi: 10.1093/cid/cis824. Epub 2012 Sep 21.

Responsible Party:	Radboud University
ClinicalTrials.gov Identifier:	NCT01288417 History of Changes
Other Study ID Numbers:	UMCN-AKF 10.05
First Posted:	February 2, 2011
Last Update Posted:	July 24, 2012
Last Verified:	July 2012

Keywords provided by Radboud University:

HIV infections; HCV infections; interaction	pharmacokinetics; raltegravir; boceprevir

Additional relevant MeSH terms:

HIV Infections; Infection; Communicable Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases	Raltegravir Potassium; HIV Integrase Inhibitors; Protease Inhibitors; HIV Protease Inhibitors; Integrase Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action