Pharmacokinetic Interactions Between Ritonavir, Amprenavir and Efavirenz and Nelfinavir, Amprenavir, and Efavirenz in People Infected with HIV

This study is currently recruiting patients.

Sponsored by

National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

In this study of pharmacokinetic interactions, (1) the effect of ritonavir on the pharmacokinetics of amprenavir; (2) the effect of efavirenz on the pharmacokinetics of amprenavir and ritonavir, and (3) the effect of efavirenz on the pharmacokinetics of amprenavir plus nelfinavir will be examined. Twenty-two patients who have a viral burden of at least 500 copies/mL on combination therapy with a protease inhibitor for at least 20 weeks will be enrolled; all will receive open-label treatment, 6 with abacavir 300 mg po BID, amprenavir 1200 mg po BID, ritonavir 200 mg po BID and efavirenz 600 mg po QD, 6 with abacavir 300 mg po BID, amprenavir 1200 mg po BID, ritonavir 500 mg po BID and efavirenz 600 mg po QD, and 10 with abacavir 300 mg po BID, amprenavir 1200 mg po BID, nelfinavir 1250 mg po BID and efavirenz 600 mg po QD. Subjects will be seen at pre-entry, baseline (Day 1), and thereafter at study weeks 1 (serial sampling), 2 (serial sampling), 4, 8, 12, 16, 24 then every 8 weeks through one year. Patients will discontinue current therapy and without a washout period will begin dosing. For the groups who will receive ritonavir, the schedule will be: dose with abacavir and amprenavir and, after one-week, serial plasma sampling will be performed for baseline amprenavir levels. Next ritonavir at the assigned dose will be added (for the full-dose, there is a rapid dose escalation) and plasma sampling will be repeated one week later; finally, efavirenz 600 mg once daily will be added and plasma sampling will again be repeated between 2 weeks after beginning the combination. For the nelfinavir group, the schedule will be: dose with nelfinavir, amprenavir, and abacavir for one week and obtain serial plasma sampling, then add efavirenz for another week and obtain serial plasma sampling. Patients with a confirmed increase in viral burden of one log or greater from baseline will end study participation. The safety and antiviral activity of each combination will also be assessed; toxicity management is outlined in the protocol. Amprenavir levels when combined with both the low and the conventional doses of ritonavir will be compared. This study is intended to provide rapid data for use in protocols of combination salvage regimens for people failing a protease-inhibitor-containing regimen.

Study Type: Clinical Trial

Official Title: Pharmacokinetic Interactions Between Ritonavir, Amprenavir and Efavirenz and Nelfinavir, Amprenavir, and Efavirenz in People Infected with HIV

Further Study Details: In this study of pharmacokinetic interactions, (1) the effect of ritonavir on the pharmacokinetics of amprenavir; (2) the effect of efavirenz on the pharmacokinetics of amprenavir and ritonavir, and (3) the effect of efavirenz on the pharmacokinetics of amprenavir plus nelfinavir will be examined. Twenty-two patients who have a viral burden of at least 500 copies/mL on combination therapy with a protease inhibitor for at least 20 weeks will be enrolled; all will receive open-label treatment, 6 with abacavir 300 mg po BID, amprenavir 1200 mg po BID, ritonavir 200 mg po BID and efavirenz 600 mg po QD, 6 with abacavir 300 mg po BID, amprenavir 1200 mg po BID, ritonavir 500 mg po BID and efavirenz 600 mg po QD, and 10 with abacavir 300 mg po BID, amprenavir 1200 mg po BID, nelfinavir 1250 mg po BID and efavirenz 600 mg po QD. Subjects will be seen at pre-entry, baseline (Day 1), and thereafter at study weeks 1 (serial sampling), 2 (serial sampling), 4, 8, 12, 16, 24 then every 8 weeks through one year. Patients will discontinue current therapy and without a washout period will begin dosing. For the groups who will receive ritonavir, the schedule will be: dose with abacavir and amprenavir and, after one-week, serial plasma sampling will be performed for baseline amprenavir levels. Next ritonavir at the assigned dose will be added (for the full-dose, there is a rapid dose escalation) and plasma sampling will be repeated one week later; finally, efavirenz 600 mg once daily will be added and plasma sampling will again be repeated between 2 weeks after beginning the combination. For the nelfinavir group, the schedule will be: dose with nelfinavir, amprenavir, and abacavir for one week and obtain serial plasma sampling, then add efavirenz for another week and obtain serial plasma sampling. Patients with a confirmed increase in viral burden of one log or greater from baseline will end study participation. The safety and antiviral activity of each combination will also be assessed; toxicity management is outlined in the protocol. Amprenavir levels when combined with both the low and the conventional doses of ritonavir will be compared. This study is intended to provide rapid data for use in protocols of combination salvage regimens for people failing a protease-inhibitor-containing regimen.   

Eligibility

Genders Eligible for Study:  Both Criteria

Adults (greater than 18 years) infected with HIV-1.

Plasma viral burden greater than 500 RNA copies/ml by bDNA method at screening visit while receiving a protease inhibitor as a part of combination therapy.

Treatment with a protease inhibitor or inhibitor(s) for the preceding 20 weeks with no protease inhibitor drug change or dose interruption for greater than 3 days in the most recent 12 weeks.

Laboratory values at screen:

hemoglobin greater than 9 g/dl;

granulocyte count greater than 900 cells/microL;

platelet count greater than 80,000 cells/microL;

AST (SGOT) less than 151 U/L

Creatine less than 2 mg/dL.

Willingness to avoid becoming pregnant or causing a pregnancy by use of effective methods which include surgical sterilization and barrier methods such as condoms and/or diaphragms. Hormonal methods of birth control are not acceptable unless barrier methods are also used because drug interactions may render their concentrations subtherapeutic. Efavirenz is potentially teratogenic and conception must be avoided.

Willing and able to provide written informed consent.

Negative serum or urine pregnancy test on the day of enrollment. Must not be lactating.

No intolerance of ritonavir or nelfinavir.

No treatment with systemic corticosteroids at greater than physiologic replacement doses, interleukins, interferons, radiation therapy or cytotoxic chemotherapeutic agents within 30 days of study drug administration or an anticipated need for radiation or chemotherapy treatment within the next 48 weeks (with the exception of local treatment for Kaposi's sarcoma).

Not suffering from serious medical conditions such as diabetes, congestive heart failure, cardiomyopathy, or other cardiac dysfunction, which, in the opinion of the investigator, would compromise the safety of the patient.

No current or anticipated therapy with other agents with documented activity against HIV-1 in vitro. Amendment 10/98

No prior exposure to the investigational agents abacavir, amprenavir or efavirenz.

No concomitant therapy at entry with corticosteroids in other than replacement doses, chemotherapy, or investigational agents.

No active, untreated opportunistic infection or other major illness that would, in the opinion of the investigator, increase the risk that adverse events might pose to the patient or might render the patient too ill to return for study visits.

Lymphoma not diagnosed within 5 years of study enrollment.

No significant substance abuse or psychiatric illness that might interfere with assessment or compliance.

No refusal to employ adequate means of birth control (non-hormonal methods); efavirenz is potentially teratofenic and conception must be avoided.

No malabsorption or other gastrointestinal dysfunction which, in the opinion of the investigator, might interfere with drug absorption or render the patient unable to take oral medication.

No history of serious rash (erythema multiforme or Stevens-Johnson syndrome) caused by nevirapine or delavirdine.

No treatment with phenobarbital, rifampin, rifabutin, midazolam, astemizole, cisapride, or triazolam unless subject is safely able to discontinue the drug(s) prior to receipt of study medications.

Must not be pregnant or lactating.

Location and Contact Information

Maryland

National Institute of Allergy and Infectious Diseases (NIAID), 9000 Rockville Pike   Bethesda,    Maryland,   20892,   United States; Recruiting

PRPL     Warren G. Magnuson Clinical Center National Institutes of Health   Bethesda,    Maryland,   20892-4754,   United States  1-800-411-1222    prpl@mail.cc.nih.gov  

More Information

Detailed Web Page

Publications that lead up to this study

Livington. 1995. Weak binding of VX-478 to human plasma proteins and implications for anti-human immunodeficiency virus therapy, J Infect Dis, Vol. 172, p. 1238

Faletto. 1997. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89, Antimicrob Agents Chemother, Vol. 41, p. 1099

Winslow. 1996. Selection conditions affect the evolution of specific mutations in the reverse transcriptase gene associated with resistance to DMP266, AIDS, Vol. 10, p. 1205

Study ID Numbers  98-I-0147

NLM Identifier  NCT00001766

Date study started August 11, 1998

Recruitment status verified  July 15, 1999

Last Updated  July 15, 1999

Back