Interaction Between Fosamprenavir/Ritonavir and a Single-dose Olanzapine (FORZA) (FORZA)

The Effect of FOsamprenavir/Ritonavir on the Pharmacokinetics of a Single-dose of the Antipsychotic Agent olanZApine (FORZA)

The effect of fosamprenavir/ritonavir (steady state) on the pharmacokinetics of a single dose of olanzapine will be studied.

In this study, the investigators expect an inducible effect of fosamprenavir/ritonavir on the CYP1A2 and UGT metabolism of olanzapine.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: fosamprenavir/ritonavir; Drug: olanzapine; Drug: olanzapine

Detailed Description

Psychosis and other mental illnesses are commonly described in patients infected with the human immunodeficiency virus (HIV). New-onset psychosis is estimated to occur in up to 15% of patients infected with HIV while 5 to 7% of patients with HIV-infection suffer from pre-existing mental illnesses including schizophrenia. Olanzapine could be an attractive antipsychotic in HIV/AIDS patients with schizophrenia.

Because olanzapine is a substrate for both UGT and CYP1A2, the pharmacokinetics of olanzapine might be influenced by low-dose ritonavir in combination with fosamprenavir. The current study is designed to test this hypothesis. Furthermore, in this study we evaluate the safety of such combination.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands
    • CRCN, Radboud Universtity Nijmegen Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject is at least 18 and not older than 55 years at screening.
• 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, electro-cardiography, results of biochemistry, haematology and urinalysis testing within 4 weeks prior to the first dose. 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 the first dose) 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), except for paracetamol.
• Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), psychiatric disorders, glaucoma, 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.
• History of narrow-angle glaucoma.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: fosamprenavir/ritonavir/olanzapine; single dose of 15 mg olanzapine after 13 days of fosamprenavir/ritonavir 700mg/100mg BID	Drug: fosamprenavir/ritonavir; 16 days 700mg/100mg RTV BID; Drug: olanzapine; 15 mg olanzapine single dose; Drug: olanzapine; 10 mg olanzapine single dose
ACTIVE_COMPARATOR: single dose olanzapine; Single dose of 10 mg olanzapine	Drug: olanzapine; 15 mg olanzapine single dose; Drug: olanzapine; 10 mg olanzapine single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
olanzapine concentrations	pharmacokinetic curve after a single dose of olanzapine alone or added to steady state fosamprenavir/ritonavir

Secondary Outcome Measures

Outcome Measure	Time Frame
adverse events	entire study

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: GlaxoSmithKline

Publications and helpful links

General Publications

• Jacobs BS, Colbers AP, Velthoven-Graafland K, Schouwenberg BJ, Burger DM. Effect of fosamprenavir/ritonavir on the pharmacokinetics of single-dose olanzapine in healthy volunteers. Int J Antimicrob Agents. 2014 Aug;44(2):173-7. doi: 10.1016/j.ijantimicag.2014.03.014. Epub 2014 May 23.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (ACTUAL): August 1, 2010
• Study Completion (ACTUAL): August 1, 2010

Study Registration Dates

• First Submitted: August 17, 2009
• First Submitted That Met QC Criteria: September 14, 2009
• First Posted (ESTIMATE): September 15, 2009

Study Record Updates

• Last Update Posted (ACTUAL): November 30, 2020
• Last Update Submitted That Met QC Criteria: November 26, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: pharmacokinetics; HIV infection; interaction
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antiemetics; Gastrointestinal Agents; Protease Inhibitors; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Olanzapine; Ritonavir; Fosamprenavir
• Other Study ID Numbers: UMCN-AKF 08.04