Effect of simultaneous versus staggered dosing on pharmacokinetic interactions of protease inhibitors

Washington, Carla

doi:10.1016/s0009-9236(03)00006-7

Cited by 17 publications

(8 citation statements)

References 18 publications

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“…The inhibition by ritonavir is commonly viewed to occur almost instantaneously and to cease when the drug has been cleared (30). It has been reported that the impact of high doses of ritonavir can last up to 48 h after the dose, despite the short half-life (3 to 5 h) (31). Switching back to standard dosing within 24 to 48 h after discontinuation of LPV/r is likely to be appropriate.…”

Section: Discussionmentioning

confidence: 99%

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Svensson

Dooley

Karlsson

2014

Antimicrob Agents Chemother

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Early initiation of antiretroviral therapy (ART) during TB therapy substantially reduces TB-related morbidity and mortality rates for coinfected patients (2, 3), and the World Health Organization recommends that ART be started as soon as possible but within 8 weeks after the initiation of TB therapy (4). Simultaneously, the global emergence and increased dissemination of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB have increased the need for novel anti-TB drugs with new mechanisms of action. Data from Eastern Europe indicate that multidrug resistance is approximately twice as common among patients with TB who have HIV, compared with patients without HIV (5), and a South African study found that 100% of patients with XDR-TB who were tested had HIV infections (6). Ensuring access to novel anti-TB compounds and determining safe and efficacious doses for coinfected patients must be priorities (7).The diarylquinoline bedaquiline (BDQ) (previously called TMC207) was recently approved for the treatment of MDR-TB and XDR-TB by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. The mechanism of action is novel and involves the inhibition of mycobacterial ATP synthase, leading to disrupted energy metabolism (8, 9). Phase II trials showed that BDQ significantly decreased the time to sputum culture conversion and increased the proportion of patients with negative culture results after 6 months of treatment, when added to a regimen of other anti-TB drugs (10,11). This treatment benefit was sustained at the end of the 120-week trial (12). The exposure-response relationship for BDQ is poorly characterized, but a recent study of early bactericidal activity detected a linear increase in bactericidal activity with increasing doses over 14 days of treatment (13). The main safety issue for BDQ is moderate QT prolongation; in addition, an unexplained increase in late deaths, compared to the placebo group, was observed in one phase II study in which all patients also received standard MDR-TB treatment, which resulted in a black-box warning in the U.S. label (12,14). In general, however, BDQ is better tolerated than other second-line TB drugs, the majority of which produce clinically significant and often treatment-limiting side effects (15). The current standard dosing regimen for BDQ is 2 weeks of 400 mg given daily, followed by 22 weeks of 200 mg administered three times per week. BDQ is extensively distributed to the tissues and has a multiphasic elimination pattern with a long terminal half-life (4 to 5 months) (16,17). It is mainly metabolized by the cytochrome P450 (CYP) enzyme CYP3A4 to a N-monodesmethyl metabolite, M2 (38). The activity of M2 against Mycobacterium tuberculosis is 3-to 6-fold weaker than the activity of BDQ, and there is concern that the metabolite may have a higher risk of toxicity (39). M2, though, circulates at much lower concentrations than the parent drug in humans. M2 is further primarily demethylated to the M3 metabolite, likely also by CYP3A4 (11,18).Ne...

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Section: Discussionmentioning

confidence: 99%

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Svensson

Dooley

Karlsson

2014

Antimicrob Agents Chemother

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“…Plasma was sampled every 2 hours for 12 hours. Plasma drug levels were determined by HPLC [33]. Doses used in this study were those that resulted in the same area under the curve as seen in humans treated with atazanavir and saquinavir.…”

Section: Methodsmentioning

confidence: 99%

Simian Immunodeficiency Virus–Infected Macaques Treated with Highly Active Antiretroviral Therapy Have Reduced Central Nervous System Viral Replication and Inflammation but Persistence of Viral DNA

et al. 2010

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Background In the era of highly active antiretroviral therapy (HAART) the prevalence of HIV-associated CNS disease has increased despite suppression of plasma viremia. Methods Using an SIV model system where all animals develop AIDS and 90% develop CNS disease by three months postinoculation (p.i.), pigtailed macaques were treated with a regimen of tenofovir disoproxil fumarate, saquinavir, atazanavir, and an integrase inhibitor starting at 12 days and euthanized at ∼175 days p.i. Results Plasma and CSF viral loads declined rapidly after initiating HAART. Brain viral RNA was undetectable at necropsy but viral DNA levels were not different from untreated SIV-infected macaques. CNS inflammation was significantly reduced, with decreased brain expression of MHC Class II and GFAP and reduced CSF CCL2 and IL-6. Brain from treated macaques had significantly lower levels of IFNβ, the Type I IFN-inducible gene myxovirus (influenza) resistance A (MxA), and indolamine 2,3-dioxygenase (IDO) mRNA suggesting suppressed immune hyperactivation, and fewer CD4+ and CD8+ T cells, suggesting reduced trafficking of T cells from peripheral blood. Brain levels of CD68 protein and TNFα and IFNγ RNA, while reduced, were not significantly lower, indicating continued CNS inflammation. Conclusions These data, generated in a rigorous, high viral load, SIV/macaque model showed benefits of HAART therapy on CNS virus replication and inflammation but no change in the levels of viral DNA and continued CNS inflammation in some individuals.

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“…Noting this activity, investigators have coadministered ritonavir with saquinavir and found markedly elevated and sustained plasma levels of saquinavir in rat and dog models. This occurred, supposedly, by inhibiting metabolism of saquinavir (10), and this combination is clinically used for individuals with HIV infection (11). On the basis of the pharmacokinetics of ritonavir, a coformulated agent containing lopinavir and ritonavir has been developed: Low doses of ritonavir enhanced the activity of lopinavir (12), and this formulation is being used for first-line therapy for some HIV-infected individuals.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Protease Inhibitor, Ritonavir

et al. 2004

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We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all-trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes. The CYP3A4 is involved in drug metabolism and acquisition of drug resistance. To clarify the drug interaction between ritonavir and other anticancer drugs, we cultured DU145 cells with docetaxel either alone or in combination with ritonavir. Ritonavir enhanced the antiproliferative and proapoptotic effects of docetaxel in the hormonally independent DU145 prostate cancer cells in vitro as measured by the clonogenic soft agar assay and detection of the activated form of caspase-3 and cleavage of poly(ADP-ribose) polymerase using Western blot analysis. Real-time PCR showed that docetaxel induced the expression of CYP3A4 at the transcriptional level, and ritonavir (10 ؊5 mol/L) completely blocked this induction. An ELISA-based assay also showed that ritonavir inhibited DNA binding activity of nuclear factor B (NFB) in DU145 cells, which is a contributor to drug resistance in cancer cells. Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.

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Effect of simultaneous versus staggered dosing on pharmacokinetic interactions of protease inhibitors

Cited by 17 publications

References 18 publications

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection

Simian Immunodeficiency Virus–Infected Macaques Treated with Highly Active Antiretroviral Therapy Have Reduced Central Nervous System Viral Replication and Inflammation but Persistence of Viral DNA

HIV-1 Protease Inhibitor, Ritonavir

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