Pharmacokinetic Study of Posaconazole Boosted Fosamprenavir (EPOS)

Study Description

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Brief Summary:

The purpose of this study is to determine the influence of posaconazole on unboosted fosamprenavir pharmacokinetics, and vice versa, in healthy volunteers.A second objective is to determine the safety of combined use of fosamprenavir with posaconazole in healthy volunteers.

Condition or disease	Intervention/treatment	Phase
HIV Infection; Fungal Infection	Drug: Posaconazole; Drug: Fosamprenavir; Drug: Ritonavir	Phase 1

Detailed Description:

Infections with fungi and yeast frequently occur in patients infected with the human immunodeficiency virus type 1 (HIV-1).

Fosamprenavir is a PI that is used to treat HIV-infection in combination with ritonavir. Once hydrolyzed to amprenavir, this substance is a substrate for CYP3A4. Ritonavir is an extremely potent inhibitor of CYP3A4 and serves as a booster of the pharmacokinetics of amprenavir. Posaconazole is a very potent CYP3A4 inhibitor and therefore might enhance amprenavir pharmacokinetics in a similar way as ritonavir.

The current study is designed to test this hypothesis. When there is an indication for antifungal therapy in an HIV-infected patient, temporal replacement of ritonavir by posaconazole would be an attractive option for combined treatment of HIV and fungal infection.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	24 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Pharmacokinetic Study of Posaconazole Boosted Fosamprenavir
Study Start Date :	January 2009
Actual Primary Completion Date :	July 2009
Actual Study Completion Date :	October 2009

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Posaconazole alone; 400mg posaconazole BID for 10 days (start on day 1 with 200mg QD, day 2 200mg BID; from day 3 onwards 400mg BID)	Drug: Posaconazole; Posaconazole oral solution 40mg/mL; 400mg BID treatment for 10 days, including dose escalation; Other Name: Noxafil
Active Comparator: Fosamprenavir ritonavir; Fosamprenavir 700mg / ritonavir 100mg BID for 10 days	Drug: Fosamprenavir; fosamprenavir tablet 700mg; 1 tablet BID for 10 days; Other Name: Telzir / Lexiva Drug: Ritonavir; Ritonavir 100mg capsule; 1 capsule BID for 10 days; Other Name: Norvir
Experimental: Fosamprenavir posaconazole; Fosamprenavir 700mg / posaconazole 400mg BID for 10 days (start on day 1 with 200mg QD, day 2 200mg BID; from day 3 onwards 400mg BID)	Drug: Posaconazole; Posaconazole oral solution 40mg/mL; 400mg BID treatment for 10 days, including dose escalation; Other Name: Noxafil Drug: Fosamprenavir; fosamprenavir tablet 700mg; 1 tablet BID for 10 days; Other Name: Telzir / Lexiva

Outcome Measures

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Primary Outcome Measures :

1. Plasma concentrations of amprenavir and posaconazole [ Time Frame: predose and at 1, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours after dosing on Study Days 10, 38 and 66. Predose on study days 1, 3, 5, 8, 29, 31, 33, 36, 57, 59, 61, and 64. ]

Secondary Outcome Measures :

1. Adverse events (safety) due to concomitant use of fosamprenavir and posaconazole [ Time Frame: period of interaction treatment ]

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 of age on the day of the first dosing.
• 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 the first dose.
• 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 the first dose) or breast-feeding female.
• Therapy with any drug (for two weeks preceding dosing), except for paracetamol.
• Subjects with an ECG with QTc interval greater than 450 ms for men, and greater than 470 ms for women at screening.
• Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), 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
Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, Netherlands

Sponsors and Collaborators

Radboud University

GlaxoSmithKline

Investigators

Principal Investigator:	David M Burger, PharmD PhD	Radboud University

More Information

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Responsible Party:	Dr. D.M. Burger, hospital pharmacist, Radboud University Nijmegen Medical Centre
ClinicalTrials.gov Identifier:	NCT00817765 History of Changes
Other Study ID Numbers:	UMCN-AKF 08.03
First Posted:	January 6, 2009
Last Update Posted:	December 1, 2009
Last Verified:	November 2009

Keywords provided by Radboud University:

interaction; pharmacokinetics; boosting; drug-drug interaction; safety

Additional relevant MeSH terms:

Infection; Communicable Diseases; HIV Infections; Mycoses; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Ritonavir; Fosamprenavir; Posaconazole	HIV Protease Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antifungal Agents; Trypanocidal Agents; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors