Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with hiv infection and active tuberculosis

Catherine V Boulanger, Elena Hollender, Karen Farrell, Jerry Jean Stambaugh, Diane Maasen, David Ashkin, Stephen Symes, Luis Espinoza, Rafael O. Rivero, Jenny J. Graham, Charles A. Peloquin

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Abstract

Background: Human immunodeficiency virus (HIV)-associated tuberculosis is difficult to treat, given the propensity for drug interactions between the rifamycins and the antiretroviral drugs. We examined the pharmacokinetics of rifabutin before and after the addition of lopinavir-ritonavir. Methods: We analyzed 10 patients with HIV infection and active tuberculosis in a state tuberculosis hospital. Plasma was collected for measurement of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir by validated high-performance liquid chromatography assays. Samples were collected 2-4 weeks after starting rifabutin at 300 mg thrice weekly without lopinavir-ritonavir, 2 weeks after the addition of lopinavir-ritonavir at 400 and 100 mg, respectively, twice daily to rifabutin at 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavirritonavir.Noncompartmental and population pharmacokinetic analyses (2-compartment open model) were performed. Results: Rifabutin at 300 mg without lopinavir-ritonavir produced a low maximum plasma concentration (Cmax) in 5 of 10 patients. After the addition of lopinavir-ritonavir to rifabutin at 150 mg, 9 of 10 had low Cmax values. Eight patients had dose increases to 300 mg of rifabutin with lopinavir-ritonavir. Most free rifabutin (unbound to plasma protein) Cmax values were below the tuberculosis minimal inhibitory concentration. For most patients, values for the area under the plasma concentration-time curve were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/US Public Health Service Study 23. One of the 10 patients experienced relapse with acquired rifamycin resistance. Conclusion. The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.

Original languageEnglish
Pages (from-to)1305-1311
Number of pages7
JournalClinical Infectious Diseases
Volume49
Issue number9
DOIs
StatePublished - Nov 1 2009

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Rifabutin
Lopinavir
Ritonavir
Tuberculosis
Pharmacokinetics
Infection
Rifamycins
Chronic Disease Hospitals
HIV
Recurrence
State Hospitals
United States Public Health Service
Virus Diseases
Treatment Failure
Drug Interactions
Blood Proteins

ASJC Scopus subject areas

  • Infectious Diseases
  • Microbiology (medical)

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Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with hiv infection and active tuberculosis. / Boulanger, Catherine V; Hollender, Elena; Farrell, Karen; Jean Stambaugh, Jerry; Maasen, Diane; Ashkin, David; Symes, Stephen; Espinoza, Luis; Rivero, Rafael O.; Graham, Jenny J.; Peloquin, Charles A.

In: Clinical Infectious Diseases, Vol. 49, No. 9, 01.11.2009, p. 1305-1311.

Research output: Contribution to journalArticle

Boulanger, CV, Hollender, E, Farrell, K, Jean Stambaugh, J, Maasen, D, Ashkin, D, Symes, S, Espinoza, L, Rivero, RO, Graham, JJ & Peloquin, CA 2009, 'Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with hiv infection and active tuberculosis', Clinical Infectious Diseases, vol. 49, no. 9, pp. 1305-1311. https://doi.org/10.1086/606056
Boulanger, Catherine V ; Hollender, Elena ; Farrell, Karen ; Jean Stambaugh, Jerry ; Maasen, Diane ; Ashkin, David ; Symes, Stephen ; Espinoza, Luis ; Rivero, Rafael O. ; Graham, Jenny J. ; Peloquin, Charles A. / Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with hiv infection and active tuberculosis. In: Clinical Infectious Diseases. 2009 ; Vol. 49, No. 9. pp. 1305-1311.
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abstract = "Background: Human immunodeficiency virus (HIV)-associated tuberculosis is difficult to treat, given the propensity for drug interactions between the rifamycins and the antiretroviral drugs. We examined the pharmacokinetics of rifabutin before and after the addition of lopinavir-ritonavir. Methods: We analyzed 10 patients with HIV infection and active tuberculosis in a state tuberculosis hospital. Plasma was collected for measurement of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir by validated high-performance liquid chromatography assays. Samples were collected 2-4 weeks after starting rifabutin at 300 mg thrice weekly without lopinavir-ritonavir, 2 weeks after the addition of lopinavir-ritonavir at 400 and 100 mg, respectively, twice daily to rifabutin at 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavirritonavir.Noncompartmental and population pharmacokinetic analyses (2-compartment open model) were performed. Results: Rifabutin at 300 mg without lopinavir-ritonavir produced a low maximum plasma concentration (Cmax) in 5 of 10 patients. After the addition of lopinavir-ritonavir to rifabutin at 150 mg, 9 of 10 had low Cmax values. Eight patients had dose increases to 300 mg of rifabutin with lopinavir-ritonavir. Most free rifabutin (unbound to plasma protein) Cmax values were below the tuberculosis minimal inhibitory concentration. For most patients, values for the area under the plasma concentration-time curve were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/US Public Health Service Study 23. One of the 10 patients experienced relapse with acquired rifamycin resistance. Conclusion. The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.",
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AU - Boulanger, Catherine V

AU - Hollender, Elena

AU - Farrell, Karen

AU - Jean Stambaugh, Jerry

AU - Maasen, Diane

AU - Ashkin, David

AU - Symes, Stephen

AU - Espinoza, Luis

AU - Rivero, Rafael O.

AU - Graham, Jenny J.

AU - Peloquin, Charles A.

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AB - Background: Human immunodeficiency virus (HIV)-associated tuberculosis is difficult to treat, given the propensity for drug interactions between the rifamycins and the antiretroviral drugs. We examined the pharmacokinetics of rifabutin before and after the addition of lopinavir-ritonavir. Methods: We analyzed 10 patients with HIV infection and active tuberculosis in a state tuberculosis hospital. Plasma was collected for measurement of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir by validated high-performance liquid chromatography assays. Samples were collected 2-4 weeks after starting rifabutin at 300 mg thrice weekly without lopinavir-ritonavir, 2 weeks after the addition of lopinavir-ritonavir at 400 and 100 mg, respectively, twice daily to rifabutin at 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavirritonavir.Noncompartmental and population pharmacokinetic analyses (2-compartment open model) were performed. Results: Rifabutin at 300 mg without lopinavir-ritonavir produced a low maximum plasma concentration (Cmax) in 5 of 10 patients. After the addition of lopinavir-ritonavir to rifabutin at 150 mg, 9 of 10 had low Cmax values. Eight patients had dose increases to 300 mg of rifabutin with lopinavir-ritonavir. Most free rifabutin (unbound to plasma protein) Cmax values were below the tuberculosis minimal inhibitory concentration. For most patients, values for the area under the plasma concentration-time curve were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/US Public Health Service Study 23. One of the 10 patients experienced relapse with acquired rifamycin resistance. Conclusion. The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.

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