Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

DiCenzo, Robert; Peterson, Derick R.; Cruttenden, Kim; Morse, Gene D.; Riggs, Garret; Gelbard, Harris A.; Schifitto, Giovanni

doi:10.1128/aac.48.11.4328-4331.2004

Cited by 55 publications

(55 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sheehan and colleagues reported a clinically significant case of decreased valproic acid concentration during lopinavir-ritonavir coadministration (18). Although we reported no evidence that lopinavir-ritonavir decreased valproic acid trough plasma concentrations during a previous study, both of our studies used a low dose of valproic acid (7). There is the potential that higher doses of valproic acid may influence the effect of minocycline on atazanavir and ritonavir or that clinically significant decreases in valproic acid exposure may be seen at higher doses.…”

Section: Discussioncontrasting

confidence: 39%

“…This study was designed in response to interest in developing combination adjunctive therapy for the treatment of HIVassociated cognitive impairment. Having previously published results that failed to show a negative influence of valproic acid on lopinavir plasma concentrations, we decided to focus this study on the potential effects of minocycline with and without valproic acid (7). Since study of the entire class of protease inhibitors is cost prohibitive, we selected atazanavir based on its frequent use as a part of highly active antiretroviral therapy at our clinic.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Effects of Minocycline and Valproic Acid Coadministration on Atazanavir Plasma Concentrations in Human Immunodeficiency Virus-Infected Adults Receiving Atazanavir-Ritonavir

DiCenzo

Peterson

Cruttenden

et al. 2008

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Minocycline and valproic acid are potential adjuvant therapies for the treatment of human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine whether minocycline alone or in combination with valproic acid affected atazanavir plasma concentrations. Twelve adult HIV-infected subjects whose regimen included atazanavir (300 mg)-ritonavir (100 mg) daily for at least 4 weeks were enrolled. Each subject received atazanavir-ritonavir on day 1, atazanavir-ritonavir plus 100 mg minocycline twice daily on days 2 to 15, and atazanavir-ritonavir plus 100 mg minocycline twice daily and 250 mg valproic acid twice daily on days 16 to 30 with meals. The subjects had 11 plasma samples drawn over a

show abstract

Section: Discussioncontrasting

confidence: 39%

mentioning

confidence: 99%

Effects of Minocycline and Valproic Acid Coadministration on Atazanavir Plasma Concentrations in Human Immunodeficiency Virus-Infected Adults Receiving Atazanavir-Ritonavir

DiCenzo

Peterson

Cruttenden

et al. 2008

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…MK-4965 exhibited an approximately four-to sixfold shift in potency in the presence of 50% HS. These results are not surprising, as MK-4965 is less protein bound (96.5%) than either EFV or ETV (Ͼ99.5%) (5,13). NVP, which is only 60% protein bound (19), did not show any shift in EC 95 for the WT virus when the serum concentration was increased from 10% to 50%.…”

Section: Discussionmentioning

confidence: 65%

Antiviral Activity of MK-4965, a Novel Nonnucleoside Reverse Transcriptase Inhibitor

Lai¹,

Munshi²,

Touch³

et al. 2009

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) converts single-stranded viral RNA into a double-stranded proviral DNA via polymerase and RNase H activities, and this is an obligate step in the HIV-1 replication cycle (15). Given the pivotal role that RT plays in the life cycle of HIV-1, the inhibition of RT has been one of the primary therapeutic strategies in suppressing the replication of HIV-1 (7, 24). Currently, two classes of RT inhibitors are available for the treatment of HIV-1 infection: nucleoside RT inhibitors (NRTIs; such as zidovudine [AZT] and lamivudine [3TC]) bind directly to the active site of RT polymerase and terminate DNA synthesis after incorporation into the newly synthesized DNA, while nonnucleoside RT inhibitors (NNRTIs; such as the first-generation NNRTIs efavirenz [EFV] and nevirapine [NVP]) bind to an allosteric site on RT.NNRTIs are noncompetitive inhibitors of HIV-1 RT that bind to a hydrophobic pocket in the p66 subunit of the p66/p51 heterodimer near the polymerase active site (17). NNRTI binding causes conformational changes within p66 that reposition the active-site residues to an inactive conformation, thereby inhibiting the chemical step of polymerization (1). Mutations of residues around the NNRTI binding pocket can interfere with NNRTI binding, thus conferring resistance to this class of compounds. Although NNRTIs are key components of effective combination regimens, like all antiretroviral agents, their effectiveness can be hampered by the emergence of clinical drug resistance. Moreover, single mutations can lead to significant reductions in susceptibility, often to all available inhibitors within the class (3, 12). For instance, the increasingly common K103N mutation (which is present in 40 to 60% of NNRTI-resistant viruses) displays significant resistance to the first-generation NNRTIs, and the Y181C mutation (which is present in 15 to 25% of NNRTI-resistant viruses) confers a high degree of resistance to both NVP and delavirdine (DLV) and a moderate degree of resistance to the recently approved second-generation NNRTI etravirine (ETV).Since NNRTIs have great therapeutic potential, extensive efforts have been made to identify novel NNRTIs that are highly active against the prevalent NNRTI-resistant viruses, that are suitable for once-daily dosing, and that have excellent safety profiles. In addition to the recently approved drug ETV, several other promising NNRTIs are in development (32).MK-4965 is a novel NNRTI containing diaryl ether and indazole moieties (Fig. 1) (34). We report here that MK-4965 displays excellent activities against not only wild-type (WT) virus but also against a broad panel of NNRTI-resistant viruses, including viruses containing the K103N and/or the Y181C mutation. In addition, MK-4965 is highly potent against viral isolates representing different HIV-1 subtypes as well as against viruses that are resistant to protease inhibitors (PIs) or NRTIs, or both. Two-drug combination studies with MK-4965

show abstract

“…As expected, efavirenz concentrations were not significantly affected by valproic acid. Although lopinavir concentrations were 38 % higher, this did not reach statistical significance [53].…”

Section: Anticonvulsant Medicationsmentioning

confidence: 84%

A Review of the Toxicity of HIV Medications II: Interactions with Drugs and Complementary and Alternative Medicine Products

et al. 2015

View full text Add to dashboard Cite

For many patients today, HIV has become a chronic disease. For those patients who have access to and adhere to lifelong antiretroviral (ARV) therapy, the potential for drugdrug interactions has become a real and life-threatening concern. It is known that most ARV drug interactions occur through the cytochrome P450 (CYP) pathway. Medications for comorbid medical conditions, holistic supplements, and illicit drugs can be affected by CYP inhibitors and inducers and have the potential to cause harm and toxicity. Protease inhibitors (PIs) tend to inhibit CYP3A4, while most nonnucleoside reverse transcriptase inhibitors (NNRTIs) tend to induce the enzyme. As such, failure to adjust the dose of coadministered medications, such as statins and steroids, may lead to serious complications including rhabdomyolysis and hypercortisolism, respectively. Similarly, gastric acid blockers can decrease several ARV absorption, and warfarin doses may need to be adjusted to maintain therapeutic concentrations. Illicit drugs such as methylenedioxymethamphetamine (MDMA, "ecstasy") in combination with PIs lead to increased toxicity, while the concomitant administration of sedative drugs such as midazolam and alprazolam in patients taking PIs can result in prolonged sedation, delayed recovery, and increased length of stay. Even supplements like St. John's Wort can alter PI concentrations. In theory, any drug that is metabolized by CYP has potential for a pharmacokinetic drug-drug interaction with all PIs, cobicistat, and most NNRTIs. When adding a new medication to an ARV regimen, use of a drug-drug interaction software and/or consultation with a clinical pharmacist/pharmacologist or HIV specialist is recommended.

show abstract

Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

Cited by 55 publications

References 33 publications

Effects of Minocycline and Valproic Acid Coadministration on Atazanavir Plasma Concentrations in Human Immunodeficiency Virus-Infected Adults Receiving Atazanavir-Ritonavir

Effects of Minocycline and Valproic Acid Coadministration on Atazanavir Plasma Concentrations in Human Immunodeficiency Virus-Infected Adults Receiving Atazanavir-Ritonavir

Antiviral Activity of MK-4965, a Novel Nonnucleoside Reverse Transcriptase Inhibitor

A Review of the Toxicity of HIV Medications II: Interactions with Drugs and Complementary and Alternative Medicine Products

Contact Info

Product

Resources

About