Pharmacokinetics Of Protease Inhibitors Research Articles

Management of Antiretroviral Therapy with Boosted Protease Inhibitors-Darunavir/Ritonavir or Darunavir/Cobicistat.

A major challenge in the management of antiretroviral therapy (ART) is to improve the patient’s adherence, reducing the burden caused by the high number of drugs that compose the treatment regimens for human immunodeficiency virus positive (HIV+) patients. Selection of the most appropriate treatment regimen is responsible for therapeutic success and aims to reduce viremia, increase the immune system response capacity, and reduce the incidence rate and intensity of adverse reactions. In general, protease inhibitor (PI) is one of the pillars of regimens, and darunavir (DRV), in particular, is frequently recommended, along with low doses of enzyme inhibitors as cobicistat (COBI) or ritonavir (RTV), by the international guidelines. The potential of clinically significant drug interactions in patients taking COBI or RTV is high due to the potent inhibitory effect on cytochrome CYP 450, which attracts significant changes in the pharmacokinetics of PIs. Regardless of the patient or type of virus, the combined regimens of DRV/COBI or DRV/RTV are available to clinicians, proving their effectiveness, with a major impact on HIV mortality/morbidity. This study presents current information on the pharmacokinetics, pharmacology, drug interactions, and adverse reactions of DRV; it not only compares the bioavailability, pharmacokinetic parameters, immunological and virological responses, but also the efficacy, advantages, and therapeutic disadvantages of DRV/COBI or DRV/RTV combinations.

The impact of SLCO1B1 polymorphisms on the plasma concentration of lopinavir and ritonavir in HIV‐infected men

* There is large interindividual variability in the pharmacokinetics of protease inhibitors (PIs) among human immunodeficiency virus (HIV)-infected individuals under highly active antiretroviral therapy. * Protease inhibitor have been recently reported to be substrates of the SLCO1B1/OATP1 drug transporter. * A single nucleotide polymorphism (SNP) in the SLCO1B1 gene (521T-->C) was associated with plasma levels of lopinavir in HIV-infected individuals. * Data on the impact of three SLCO1B1 SNPs (521T-->C, 388A-->G, 463C-->A) on the trough plasma concentration of lopinavir and ritonavir in a cohort of 99 adult HIV-infected Brazilian men under stable highly active antiretroviral therapy. * Evidence that carriers of the 521C allele display significantly higher lopinavir, but not ritonavir plasma concentrations relative to the wild-type TT genotype. * No effect of either 388A-->G or 463C-->A SNPs on lopinavir or ritonavir plasma concentrations. * Further studies are required to confirm the clinical significance of the association between the SLCO1B1521T-->C polymorphism and lopinavir pharmacokinetics. To investigate possible associations between three SLCO1B1 single nucleotide polymorphisms (388A-->G, 463C-->A, 521T-->C) and lopinavir/ritonavir plasma concentrations. The study included 99 human immunodeficiency virus-infected men on stable highly active antiretroviral therapy containing lopinavir/ritonavir. Trough concentrations of lopinavir and ritonavir in plasma were quantified using liquid chromatography-tandem mass spectrometry. Genotyping of SLCO1B1388A-->G, 463C-->A and 521T-->C polymorphisms was performed by allelic discrimination using real-time polymerase chain reaction. The trough concentration of lopinavir in plasma is significantly associated with SLCO1B1521T-->C genotypes (P= 0.03). There is a significant trend for increasing concentrations of lopinavir from TT to TC to CC genotypes (P= 0.02). Carriers of the 521C allele display significantly higher lopinavir plasma concentrations relative to the wild-type TT genotype (P= 0.03). Reduced uptake of lopinavir by hepatocytes in carriers of the 521C allele may account for these results, but further studies to confirm the clinical importance of SLCO1B1 polymorphisms in lopinavir pharmacokinetics are warranted.

Tenofovir: farmacología e interacciones

Tenofovir is a nucleotide analogue and consequently its mechanism of action differs from that of nucleoside analogues. This drug is administered orally in the form of disoproxil ester, which is deesterified to achieve a bioavailability of more than 20%. This bioavailability slightly increases if tenofovir is taken with a fat-rich meal. This drug has broad tissue distribution, aided by its small molecular size and very low protein binding, and is eliminated as unchanged drug in the urine through glomerular filtration and active tubular secretion. Because of this latter characteristic, dosage adjustments are required in patients with renal insufficiency. The intracellular half-life of tenofovir is more than 10 times greater than the plasma half-life. Because of the pharmacokinetic profile of tenofovir, interactions with other drugs are scarce. Within the class of antiretroviral agents, an increase in the bioavailability of didanosine has been described, leading to the recommendation that the dose of didanosine be reduced when used in combination with tenofovir. Tenofovir can be used without adjustments with other nucleoside and nonnucleoside reverse transcriptase inhibitors. Equally, tenofovir seems to have no effect on the pharmacokinetics of protease inhibitors although these latter agents may produce a slight increase in the bioavailability of tenofovir, which seems to be of little clinical relevance. The absence of interactions with other non-antiretroviral agents has been reported.

Differences in the pharmacokinetics of protease inhibitors between healthy volunteers and HIV-infected persons

Pharmacokinetic and drug-drug interaction studies are conducted in both healthy volunteers and the target population (HIV-infected patients), but there is little discussion of the potential for differences in drug disposition between the two groups. It is important to recognize that the pharmacokinetics of drugs may be altered in HIV-infected persons as compared with healthy individuals. The aim of this review is to highlight some of the important differences in drug handling between healthy volunteers and HIV-infected individuals, focusing on protease inhibitors. Studies aimed at characterizing disparities in pharmacokinetics between healthy volunteers and HIV patients are lacking. Data suggest that concentrations of some protease inhibitors are lower in HIV patients than in HIV-negative volunteers (atazanavir and tipranavir), but generally comparisons are made across studies and study centres, and so multiple variables, such as differences in food and study design, can influence findings. We have conducted an 'in-house' analysis, comparing atazanavir, lopinavir and saquinavir between HIV-infected patients and healthy volunteers enrolled in the same study centre with similar study designs. For atazanavir the current data are quite convincing that concentrations are lower in HIV-infected patients than in healthy individuals, but for others it is not so clear. The 'in-house' analyses for atazanavir, lopinavir and saquinavir attempted to address some of the difficulties with cross-study comparisons, but it should be noted that subject numbers were small. Physiological changes resulting from HIV disease can influence drug pharmacokinetics and the underlying mechanisms remain to be elucidated.

Drug Interactions between HIV Protease Inhibitors and Acid-Reducing Agents

Maximal efficacy of protease inhibitor-based antiretroviral therapy for HIV/AIDS requires adequate drug absorption and bioavailability. However, the use of acid-reducing agents in patients treated with highly active antiretroviral therapy is common and may induce clinically significant drug-drug interactions that alter plasma protease inhibitor concentrations, which may lead to inadequate viral suppression or adverse events. As plasma antiretroviral concentrations are not routinely monitored in patients, it is important to understand the risk of these interactions and counsel patients appropriately, thereby maximizing antiviral potential and preventing the development of antiretroviral resistance. We therefore reviewed the literature to assess the current understanding of the effect of various acid-reducing agents on the pharmacokinetics of protease inhibitors. The bioavailability of fosamprenavir, indinavir, lopinavir, nelfinavir and tipranavir has been reported to be negatively affected to varying degrees by certain acid-reducing agents. The negative effect on atazanavir concentrations observed in healthy subjects was more attenuated in HIV-infected patients and warrants further investigation. While the plasma concentration of saquinavir increased, short-term studies in healthy subjects did not indicate an increased risk of adverse events. No clinically relevant changes in plasma concentrations of darunavir occurred when combined with acid-reducing agents. The individual effect of acid-reducing agents on protease inhibitor concentrations is difficult to predict because of the large interpatient variability of plasma concentrations with some protease inhibitors. Studies suggest that some of the interactions between protease inhibitors and acid-reducing agents may be mitigated by temporal separation of dose administration. Educating patients about the importance of reporting the use of any acid-reducing agents, whether prescription or over-the-counter, is essential to optimizing the treatment of HIV disease, as is the need for care providers and patients to agree upon strategies for managing gastric symptoms and HIV disease simultaneously. Clinicians should be aware of the potential drug-drug interactions between some protease inhibitors and acid-reducing agents.

Therapeutic Drug Monitoring: A Tool to Individualize Highly Active Antiretroviral Therapy in HIV Infected Patients

In HIV-infection, therapeutic drug monitoring (TDM) has been proposed to optimize highly active antiretroviral therapy (HAART) response. Pharmacokinetics of protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) efavirenz and nevirapine have been proved suitable for monitoring their plasma drug levels. In contrast, nucleoside reverse transcriptase inhibitors (NRTI) contain lack of a certain correlation between plasma levels and drug efficacy. Currently, TDM under HAART is limited by some uncertainty which pharmacokinetic predictor to prefer and on which drug concentration or range to rely on. In a therapy naive patient trial (ATHENA) on indinavir or nelfinavir based drug regimens, the study arm with use of TDM resulted in prevention of virological failure or treatment discontinuation due to drug toxicity. Current data ascribed increasing importance to TDM in ritonavir boosted PI combinations especially for lopinavir, atazanavir and fosamprenavir. Besides, further applications are proposed in selected patients groups (i.e. children, pregnancy, renal or hepatic dysfunction, weight loss) to confirm adequate drug concentrations and manage drug-drug- interactions. PI double-boosting in salvage regimens in patients with multiple NRTI associated mutations should also require TDM for handling dose adjustments, moreover, treatment experienced patients might benefit from TDM in combination with viral resistance testing. Limitations to the application of TDM are considered as non standardized procedures or techniques permitted to correlate pharmacological and virological data therefore, an approach towards standardization is needed. So far the inhibitory quotient (IQ) (necessitating phenotypical resistance testing) or the genotypic inhibitory quotient (GIQ) (referring to the number of viral mutations using a genotypic resistance test), could become increasingly important in this context. In assessing adherence, TDM allows to confirm the correct medication intake, but only the last few doses taken by a patient will be reflected. Without TDM, numerous interactions by co-administered drugs (antibiotics, antacid drugs, hypnotics, herbals, life-style drugs) turn out to possibly lead to obscure interpretations and individual medical care remains elusive. Currently, the interpretation of PI and NNRTI drug levels is based on increasing experience using TDM. Even though TDM in HAART is not the gold standard of care, yet, it provides security in guiding patients on an individual therapy and might be linked with pharmacogenomics in resource-rich countries. Keywords: Therapeutic Drug Monitoring, HAART, PI, NNRTI, HIV

Absence of circadian variation in the pharmacokinetics (PK) of lopinavir/ritonavir (LPV/R) in a once-daily (QD) dosing regimen in hiv-1-infected subjects

Background Previous studies suggest a circadian phase dependency in the PK of protease inhibitors. This may have practical implications, especially for qd regimens. This study explored the PK of LPV/r 800/200 mg qd after am versus pm dosing. Methods A randomized two-way cross-over study in HIV+ subjects taking LPV/r bid + 2 NRTIs. 24h PK were assessed after 2 weeks of LPV/r qd at 8 am and 7 pm, resp. LPV/r was taken with a standardized meal (800 kCal, 30% from fat) after fasting for 5 h. LPV/r concentrations were measured by LC/MS/MS. PK were analyzed by noncompartmental methods. Results 12 subjects completed the study (all men, mean age/weight 44 yrs/80 kg). The median (IQR) LPV AUC24h, Cmax and C24h after am and pm dosing was 143 (100-235) h*mg/L, 12.8 (8.8-19.6) mg/L, 1.2 (0.6-2.4) mg/L, and 171 (122-230) h* mg/L, 12.9 (8.4-16.9) mg/L, 1.0 (0.4-1.7) mg/L, resp. The intra- and intersubject variability in the LPV AUC24h was 19 and 39%, resp. The geometric mean ratio (GMR, am/pm) and 90% CI of the LPV AUC24h, Cmax, and C24h was 0.91 (0.78-1.05), 1.09 (0.99-1.21), and 1.24 (0.78-1.97), resp. For 11/12 subjects RTV concentrations remained below 2.1 mg/L. The GMR (90% CI) of the RTV AUC24h, Cmax, and C24h was 0.94 (0.81-1.11), 1.35 (1.09-1.68), and 1.04 (0.7–1.54), resp. Conclusion No clinically relevant differences were observed in the PK of LPV/r after am or pm dosing with food. This suggests that LPV/r qd can be taken in the morning or evening, which may facilitate adherence. Clinical Pharmacology & Therapeutics (2004) 75, P35–P35; doi: 10.1016/j.clpt.2003.11.133

Role of therapeutic drug monitoring for protease inhibitors.

To review the role of therapeutic drug monitoring (TDM) for protease inhibitors in the treatment of HIV infection. Primary articles were identified using MEDLINE (1966-October 2000), EMBASE (1987-October 2000), AIDSLINE (1980-October 2000), Current Contents, PubMed, and Medscape. Further articles were identified from bibliographic review of primary articles and review papers. Abstracts presented at the World AIDS Conference, Interscience Conference on Antimicrobial Agents and Chemotherapy, and Conference on Retroviruses and Opportunistic Infections were also identified from 1997 to 2000. All English-language, prospective clinical trials, as well as selected retrospective studies and case series, pertaining to therapeutic drug monitoring of protease inhibitors were included. A number of clinical studies have found a good relationship between concentration and pharmacologic response and/or toxicity as well as wide interpatient variability in the pharmacokinetics of protease inhibitors. There also is some preliminary evidence of the usefulness of plasma drug concentrations to guide dosage adjustments of protease inhibitors in patients with liver dysfunction. Furthermore, there is preliminary evidence of a relationship between drug concentrations and resistance. A number of clinical studies support the usefulness of TDM of protease inhibitors. However, before TDM can be of the most value, further evaluation requires simplified and standardized assays to be performed routinely by clinical laboratories; determination of the appropriate target concentration and therapeutic range, as well as the best predictor of pharmacologic response; and refined interpretation of plasma drug concentrations. Randomized, controlled clinical trials of patient outcomes are needed to assess the clinical utility of TDM for protease inhibitors.

Combination of Protease Inhibitors for the Treatment of HIV-1-Infected Patients: A Review of Pharmacokinetics and Clinical Experience

The use of highly active antiretroviral therapy, the combination of at least three different antiretroviral drugs for the treatment of HIV-1 infection, has greatly improved the prognosis for HIV-1-infected patients. The efficacy of a combination of a protease inhibitor (PI) plus two nucleoside analogue reverse transcriptase inhibitors has been well established over a period of up to 3 years. However, virological treatment failure has been reported in 40-60% of unselected patients within 1 year after initiation of a PI-containing regimen. This observation may, at least in part, be attributed to the poor pharmacokinetic characteristics of the PIs. Given as a single agent the PIs have several pharmacokinetic limitations; relatively short plasma-elimination half-lives and a modest and variable oral bioavailability, which is, for some of the PIs, influenced by food. To overcome these suboptimal pharmacokinetics, high doses (requiring large numbers of pills) must be ingested, often with food restrictions, which complicates patient adherence to the prescribed regimen. Positive drug-drug interactions increase the exposure to the PIs, allowing administration of lower doses at reduced dosing frequencies with less dietary restrictions. In addition to increasing the potency of an antiretroviral regimen, combinations of PIs may enhance patient adherence, both of which will contribute to a more durable suppression of viral replication. The favourable pharmacokinetics of PIs in combination are a result of interactions through cytochrome P450 3A4 (CYP3A4) isoenzymes and, possibly, the multi-drug transporting P-glycoprotein (P-gp). Antiretroviral synergy between PIs and non-overlapping primary resistance patterns in the HIV-1 protease genome may further enhance the antiretroviral potency and durability of combinations of PIs. Many combinations contain ritonavir because this PI has the most pronounced inhibiting effects on CYP3A4. The combination of saquinavir and ritonavir, both in a dose of 400 mg twice-a-day, is the most studied double PI combination, with clinical experience extending over 3 years. Combination of a PI with a low dose of ritonavir (< or = 400 mg/day), only to boost its pharmacokinetic properties, seems an attractive option for patients who cannot tolerate higher doses of ritonavir. A recently introduced PI, lopinavir, has been co-formulated with low-dose ritonavir, which allows for a convenient three-capsules, twice-a-day dosing regimen. In an attempt to prolong suppression of viral replication combinations of PIs are becoming increasingly popular. However, further clinical studies are needed to identify the optimal combinations for treatment of antiretroviral naive and experienced HIV-1-infected patients. This review covers combinations of saquinavir, indinavir, nelfinavir, amprenavir and lopinavir with different doses of ritonavir, as well as the combinations of saquinavir and indinavir with nelfinavir.