Pharmacokinetic Interactions Between Telaprevir and Un-boosted Atazanavir

Pharmacokinetic Interactions Between Telaprevir and Un-boosted Atazanavir in HIV/HCV-co-infected Patients Under Treatment for Genotype 1 Chronic Hepatitis C.

Hypothesis: the Telaprevir(TVR) plasma levels (750 mg q8h or 1125 mg/12h )will not be affected when co-administered with un-boosted Atazanavir (ATV) 200 mg q12h plus two analogues (NRTIs) in HCV/HIV-co-infected patients.

Study Overview

• Status: Completed
• Conditions: HIV Infection; Hepatitis C, Chronic
• Intervention / Treatment: Drug: Ritonavir withdrawal, atazanavir 200 mg/12h; Drug: Telaprevir interactions

Detailed Description

Objectives

1. Primary Outcome Measures: evaluate the changes in the plasma pharmacokinetic parameters (Cmax, Cmin, AUC, t 1/2, and Cl) of Telaprevir (TVR) administered at 750 mg/8h together with un-boosted Atazanavir (200 mg/12h), taking as reference the pharmacokinetic parameters observed when TVR is administered with Atazanavir/ritonavir (300/100 mg/day)
2. To assess the changes in the plasma pharmacokinetic parameters of Atazanavir administered as 200 mg/12h with respect to its administration as 300/100 mg/day when administered together with TVR (750 mg/8h or 1125 mh/12h).

Method: open labelled clinical trial with a planned duration of 24 weeks in which 14 HIV/Hepatitis C virus genotype 1 patients under treatment with pegylated α-interferon, Ribavirin and Telaprevir will be enrolled. A 24 hours pharmacokinetic profile will be obtained after a supervised drug intake while taking TVR and ATV/rtv. Afterwards, the patients will take un-boosted ATV 200 mg bid for 7 - 10 days. Subsequently, a new pharmacokinetic profile will be obtained.

• Study Type: Interventional
• Enrollment (Anticipated): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• Spain
  • Seville, Spain, 41013
    • Hospital Universitario Virgen Del Rocio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients over 18 years old co-infected with HIV and genotype 1 HCV under treatment with pegylated α-interferon, Ribavirin and Telaprevir according to the recommendations of the Spanish Agency of Medicines and Health Products.
• Informed consent of the patient.

Exclusion Criteria:

• The usual exclusion criteria in clinical practice to start the treatment with these drugs (pegylated α-interferon, Ribavirin, Telaprevir and atazanavir) according to the Spanish and international recommendations (Spanish Agency of Medicines and Health Products,European Association for the Study of the Liver Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2011. Consensus Document of Gesida/Spanish Plan on Aids regarding the antiretroviral treatment in adults infected with the human immunodeficiency virus [Updated January 2012]).
• Concomitant use of drugs or medicinal products that could alter the pharmacokinetics of TVR or ATV.
• Medical records suggesting malabsorption or presence of diarrhea (>3 depositions/day) that could interfere with the absorption of the studied drugs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Telaprevir interactions; Telaprevir 750 mg/8h or 1125 mg/12h (+ pegIFN alfa and ribavirin) plus Atazanavir/ritonavir 300/100 mg/24. Pharmacokinetic profile on day 0. Intervention: Ritonavir will be withdrawn and the atazanavir dose increased to 200 mg/12h for days 1 to 7. On day 8: a morning dose of Telaprevir (750 mg or 1125 mg) plus Atazanavir 200 mg. Pharmacokinetic profile for 12 hours

Drug: Ritonavir withdrawal, atazanavir 200 mg/12h; Other Names: Norvir; Reyataz; Incivo; Drug: Telaprevir interactions; Other Names: Norvir; Reyataz; Incivo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in pharmacokinetic parameters of TVR	The Telaprevir peak concentrations (Cmax), trough levels (Cmin) at 8 or 12 hours, the areas under the curves over the dosing interval (AUC0-τ), and half-life during the elimination phase (t½ β) will be compared between days 0 and 7 as geometric mean ratios (GMRs) and their 90% CIs using day 0 values as reference. The differences in pharmacokinetic parameters between the regimens will be considered significant when the interval between low and high 90% CI did not include the value 1.0.	7 - 10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in pharmacokinetic parameters of ATV	The Atazanavir peak concentrations (Cmax), trough levels (Cmin) at 12 or 24 hours, the areas under the curves over the dosing interval (AUC0-τ), and half-life during the elimination phase (t½ β) will be summarized as geometric means (GM) and will be compared between days 0 and 7 as geometric mean ratios (GMRs) and their 90% CIs using day 0 values as reference. The differences in pharmacokinetic parameters between the regimens will be considered significant when the interval between low and high 90% CI did not include the value 1.0.	7 - 10 days

Collaborators and Investigators

• Sponsor: Hospitales Universitarios Virgen del Rocío
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Luis F Lopez-Cortes, MD, PhD., Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla. Spain.

Publications and helpful links

General Publications

• Gutierrez-Valencia A, Ruiz-Valderas R, Ben-Marzouk-Hidalgo OJ, Torres-Cornejo A, Espinosa N, Castillo-Ferrando JR, Viciana P, Lopez-Cortes LF. Telaprevir and ribavirin interaction: higher ribavirin levels are not only due to renal dysfunction during triple therapy. Antimicrob Agents Chemother. 2015;59(6):3257-62. doi: 10.1128/AAC.04795-14. Epub 2015 Mar 23.
• Gutierrez-Valencia A, Ruiz-Valderas R, Torres-Cornejo A, Viciana P, Espinosa N, Castillo-Ferrando JR, Lopez-Cortes LF. Role of ritonavir in the drug interactions between telaprevir and ritonavir-boosted atazanavir. Clin Infect Dis. 2014 Jan;58(2):268-73. doi: 10.1093/cid/cit693. Epub 2013 Oct 21.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: December 29, 2012
• First Submitted That Met QC Criteria: March 23, 2013
• First Posted (Estimate): March 27, 2013

Study Record Updates

• Last Update Posted (Estimate): April 22, 2013
• Last Update Submitted That Met QC Criteria: April 19, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: Chronic hepatitis C; Drug interaction; HIV-infection
• Additional Relevant MeSH Terms: Digestive System Diseases; 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; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; HIV Infections; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Atazanavir Sulfate
• Other Study ID Numbers: LLC-TEL-2012-1; 2012-002515-25 (EudraCT Number)