Population pharmacokinetics of lopinavir in combination with ritonavir in HIV-1-infected patients.

AIMS: To develop a population pharmacokinetic model for lopinavir in combination with ritonavir, in which the interaction between both drugs was characterized, and in which relationships between patient characteristics and pharmacokinetics were identified. METHODS: The pharmacokinetics of lopinavir in combination with ritonavir were described using NONMEM (version V, level 1.1). First, ritonavir data were fitted to a previously developed model to obtain individual Bayesian estimates of pharmacokinetic parameters. Hereafter, an integrated model for the description of the pharmacokinetics of lopinavir with ritonavir was designed. RESULTS: From 122 outpatients 748 lopinavir and 748 ritonavir plasma concentrations were available for analysis. The interaction between the drugs was described by a time-independent inverse relationship between the exposure to ritonavir over a dosing-interval and the apparent clearance (CL/F) of lopinavir. The model parameters volume of distribution and absorption rate constant were 61.6 l (95% prediction interval (PI) 22.4, 83.7) and 0.564 h(-1) (95% PI 0.208, 0.947), respectively. The model yielded a theoretical value for the CL/F of lopinavir without ritonavir of 14.8 l h(-1) (95%PI 12.1, 20.1), which translates to a value of 5.73 l h(-1) in the presence of ritonavir. The only factor with significant effect on the pharmacokinetics was concurrent use of non-nucleoside reverse transcriptase inhibitors (NNRTI), which increased the CL/F of lopinavir by 39% (P < 0.001). CONCLUSIONS: We have developed a model that has defined a time-independent inverse relationship between the exposure to ritonavir and the CL/F of lopinavir, and provided an adequate description of the pharmacokinetic parameters for the latter. Concomitant use of the NNRTIs efavirenz and nevirapine increased the CL/F of lopinavir.

Pharmacokinetics of low-dose doxorubicin and metabolites in patients with AIDS-related Kaposi sarcoma.

PURPOSE: Systemic chemotherapy is the treatment of choice for AIDS-related advanced Kaposi sarcoma. One principal schedule combines adriamycin (doxorubicin), bleomycin, and vincristine (ABV). We analysed the plasma concentrations of low-dose doxorubicin (Dx) and its metabolites doxorubicinol, 7-deoxydoxorubicinone, doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinolone in AIDS-patients to define patient-group and dose-specific pharmacokinetic parameters. MATERIALS AND METHODS: A previously described high-performance liquid chromatographic (HPLC) method and a population approach with non-linear mixed effects modelling (NONMEM) were used for analysis and subsequent modelling of the time-concentration data of low-dose Dx and metabolites in seven patients with AIDS-related advanced Kaposi sarcoma. Patients received Dx 20 mg m(-2), bleomycin 15 U m(-2) and vincristine 2 mg as a 30-min intravenous infusion each. Blood samples were collected up to 72 h after the start of Dx treatment. WinNonlin software version 4.1 was used for non-compartmental analysis and NONMEM software version V for compartmental analysis. Covariate analysis was performed for various clinical and laboratory parameters. RESULTS: Non-compartmental analysis yielded an area under the plasma concentration-time curve (AUC) for Dx of 566 mug h L(-1), a maximum plasma concentration (c(max)) of 599 mug L(-1) and an elimination half-life (t(1/2)) of 30.8 h. Compartmental analysis resulted in a two-compartment model with first-order elimination, which best fitted the concentration-time data. Model estimate for Dx clearance was 61.8 L h(-1), for intercompartmental clearance (Q) 112 L h(-1), for the volume of the central compartment (V(1)) 23.3 L, and for the volume of the peripheral compartment (V(2)) 1,130 L. Metabolite data could adequately be estimated by NONMEM using single-compartment models. Graphical plots of residuals versus time for all metabolites yielded no evidence of non-linear pharmacokinetic behaviour. Laboratory parameters of liver and renal function were all in the normal range and their inclusion in the pharmacokinetic model did not improve data fit. A final jack-knife analysis was performed. CONCLUSIONS: Concentration-time data for low-dose Dx and metabolites in the ABV-regimen are best described by a two-compartment model with first-order elimination. The results confirm that the aglycones doxorubicinone, 7-deoxydoxorubicinone, and doxorubicinolone can be reliably detected in the studied patient group and implemented into a common metabolic model. Model estimates suggest that pharmacokinetic parameters are similar for low-dose Dx and higher-dosed Dx. As the role of the aglycones is still poorly understood, despite their potential clinical relevance, their analysis should be implemented in future pharmacokinetic and pharmacodynamic studies of Dx.

Evaluation of clinical pharmacist interventions on drug interactions in outpatient pharmaceutical HIV-care.

OBJECTIVE: To evaluate the usefulness of intervention in drug interactions of antiretroviral drugs with coadministered agents by a clinical pharmacist in outpatient HIV-treatment. METHODS: The study design included two intervention arms (A and B), which were both preceded by a control observation period. In arm A, a complete list of the currently used drugs, extracted from pharmacy records was provided to the treating physician. In arm B the same list was provided but with a notification when a drug interaction was present and an advice how to handle this. The infectious disease specialist obtained the information before the patient's visit to the outpatient clinic (time point 0). Three months prior (time point -3) and 3 months after (time point +3) the intervention, pharmacy records were also screened for drug interactions. The number of drug interactions (total and per patient) was determined at the three different time points (-3, 0, +3). In addition, drug interactions encountered at time points -3 and 0 were checked for their presence at time points 0 and +3, respectively, for both intervention arms. RESULTS: Arms A and B included 115 and 105 patients, respectively. Patient characteristics of both intervention arms were similar at time point 0. The number of interactions and the number of patients with interactions were similar in both intervention arms at time point 0. There were 42 and 40 potential drug interactions in 30 and 24 patients in arms A and B, respectively. The reduction in the number of interactions per patient over time and after intervention was small but significant, and was equal in both intervention arms. The advice of the clinical pharmacist had thus no additional value. CONCLUSION: Both interventions were effective in reducing the number of drug interactions per patient. The advice of a clinical pharmacist was, however, redundant in the studied setting.

Prognostic factors for the clinical effectiveness of fluconazole in the treatment of oral candidiasis in HIV-1-infected individuals.

OBJECTIVE: To identify prognostic factors for the clinical effectiveness of fluconazole in HIV-1-infected patients with oropharyngeal candidiasis. DESIGN AND SETTING: The study was designed as a prospective, open label, non-comparative, dose escalating, single centre trial. PATIENTS AND METHODS: Thirty-four HIV-1-infected patients with oropharyngeal Candida infection were treated with 50 or 100mg fluconazoleday(-1), depending on the clinical manifestation (erythematous or pseudomembranous). The dose was doubled weekly until clinical cure. The predictive value of potential prognostic factors for the duration of treatment and cumulative fluconazole dose until cure was studied: exposure to fluconazole, previous use of fluconazole, the use of antiretroviral drugs, the CD4(+) cell count, erythematous or pseudomembranous appearance, the minimum inhibitory concentration (MIC) for fluconazole of the isolated Candida strain, and xerostomia. RESULTS: Twenty-eight patients (with 30 episodes of oropharyngeal candidiasis) were evaluated. Twenty-five episodes were cured within 1-week of treatment, the remaining five episodes were cured within 2 weeks. No predictive value for any of the studied factors on the duration of fluconazole treatment or the cumulative fluconazole dose until cure was demonstrated. CONCLUSION: Because of the high susceptibility to fluconazole and the positive clinical outcome, the variation in outcome measurements was too modest to establish a significant relationship between any of the investigated potentially prognostic factors and the cumulative fluconazole dose and the duration of treatment to reach cure. On the other hand it can be concluded, that fluconazole is very effective in patients with advanced HIV infection and low CD4(+) cell counts, even if they are not using antiretroviral agents.

Itraconazole solution: summary of pharmacokinetic features and review of activity in the treatment of fluconazole-resistant oral candidosis in HIV-infected persons.

The clinical pharmacology of itraconazole is presented in relation to its use in the treatment of fluconazole-resistant oropharyngeal candidosis. The oral solution is a new formulation of itraconazole in which itraconazole is solubilised with the use of cyclodextrin. This formulation has a higher bioavailability and leads to higher local concentrations in the oral cavity which are advantages over the solid capsule formulation. Literature, in which the use of itraconazole oral solution was described to treat fluconazole-resistant oral candidosis, is reviewed. In about 55% of the patients signs and symptoms of oral candidosis were resolved after treatment with itraconazole oral solution. Although all the reviewed studies lack data to objectively qualify all the included patients as having a fluconazole-resistant candidosis, the authors conclude, that based on the available information itraconazole oral solution 100 or 200mg twice daily can be effective for fluconazole-resistant oropharyngeal candidosis (OPC) and should be considered prior to salvage therapy with intravenous amphotericin B. The use of itraconazole, however, requires careful monitoring of the patients co-medication for potential serious drug-drug interactions.

Detection of late pp67-mRNA by NASBA in peripheral blood for the diagnosis of human cytomegalovirus disease in AIDS patients.

OBJECTIVE: To evaluate the value of late-pp67-mRNA nucleic acid sequence-based amplification (NASBA) in comparison to DNA-PCR, blood culture and pp65-antigenemia assay for the detection of human cytomegalovirus (HCMV) disease in HIV-infected patients. METHODS: The results of pp67-mRNA NASBA, DNA-PCR, culture and pp65-antigenemia assay were compared in 402 whole blood specimens of 98 HIV-infected patients with a low CD4 lymphocyte count who had not yet received highly active antiretroviral therapy (HAART). Thirty-seven samples were obtained from 30 patients with a diagnosis of HCMV disease and 365 samples from 68 patients without HCMV disease. RESULTS: The highest agreement of test results was observed between pp67-mRNA NASBA and quantitative pp65-antigenemia, with a threshold of nine antigen-positive cells/10(5) leukocytes (kappa-value 0.70, 95% CI=0.58-0.82). The sensitivity of pp67-mRNA NASBA for the diagnosis of HCMV disease (59.3%) was identical to that of the quantitative pp65-antigenemia assay, higher than that of the blood culture (48.2%) but lower than that of the DNA-PCR (77.8%). Pp67-mRNA NASBA (92.3%), quantitative pp65-antigenemia assay (92.3%) and blood culture (93.9%) were highly specific for the diagnosis of HCMV disease and as a result, had a higher positive predictive value (76.2, 76.2 and 76.5%, respectively) than the qualitative DNA-PCR (58.3%) and the qualitative pp65-antigenemia assay (47.6%). CONCLUSION: pp67-mRNA NASBA, an easy and rapid to perform assay, well-standardised by virtue of co-amplified internal system control RNA, provides a high specificity and positive predictive value for the diagnosis of HCMV disease in HIV-infected patients, comparable to that of the quantitative pp65-antigenemia assay and blood culture.

Development of hepatitis B virus resistance for lamivudine in chronic hepatitis B patients co-infected with the human immunodeficiency virus in a Dutch cohort.

INTRODUCTION: With the introduction of HAART, the HIV-1 has turned from a lethal into a chronic infection in the majority of patients. In homosexual populations, 20% of HIV-1 infected patients suffer from a chronic HBV infection, which may eventually lead to complications of the liver disease because of prolonged survival. Lamivudine is effective in reducing both HIV-1 and HBV viral replication. However, resistance for lamivudine may complicate the course of the HBV disease in HIV-1-infected patients. We, therefore, conducted a retrospective study in HIV-1-HBV co-infected patients on lamivudine therapy. PATIENTS AND METHODS: All HIV-1-HBV co-infected patients who were treated with lamivudine for over 6 months in five major referral clinics in The Netherlands with HBV DNA above 2.0 x 10(5) geq ml(-1) at baseline, were evaluated. Retrospectively, the course of HBV DNA in available serum samples was established. If HBV DNA was detectable with the sensitive PCR-assay, YMDD-analyses of the polymerase gene of the hepatitis B virus was executed with the INNO-LiPA-DR-strip. RESULTS: Forty-six patients were evaluated. The median level of HBV DNA at start of lamivudine therapy was 1.31 x 10(9) geq ml(-1) (range 3.5 x 10(5) - 2.0 x 10(10), n=43). Of three patients no baseline sample was available, but since HBV DNA was still above 2.0 x 10(5) geq ml(-1) at week 3, 7 and 11, these patients were included. Median duration of lamivudine therapy was 97 weeks (range 27-263). The percentage of detected mutations was 25 and 52% at 1 and 2 years, respectively. Twenty-two patients ultimately developed a mutation. Both baseline Body Mass Index (BMI) and the decrease in CD4 cell count as a time dependent factor were significantly related to the emergence of mutations. In 10 out of 12 evaluated patients, HBV DNA levels returned to baseline level or even above baseline level after the development of mutant virus. One patient (5%) developed a flare of serum transaminases (ALT>10 x ULN) 24 weeks after first detection of variant virus. CONCLUSION: There is a linear time-dependent appearance of HBV mutations for lamivudine in our population. In a minority of patients (5%), development of a mutation was followed by a significant elevation of serum transaminases. A decline in CD4 cell count, which may indicate less response to HAART, induces a faster emergence of mutations and close surveillance of HBV co-infected patients on therapy may be indicated due to the prolonged survival of HIV-1 patients.

Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study.

BACKGROUND: Adherence to highly active antiretroviral therapy (HAART) for human immunodeficiency syndrome type 1 (HIV-1) infection is essential to sustain viral suppression and prevent drug resistance. We investigated adherence to HAART among patients in a clinical cohort study. METHODS: Patients receiving HAART had their plasma concentrations of protease inhibitors or nevirapine measured and completed a questionnaire on adherence. We determined the percentage of patients who reported taking all antiretroviral medication on time and according to dietary instructions in the past week. Drug exposure was compared between patients reporting deviation from their regimen and fully adherent patients. Among patients who received HAART for at least 24 weeks, we assessed the association between adherence and virologic outcome. RESULTS: A total of 224 of 261 eligible patients completed a questionnaire. Forty-seven percent reported taking all antiretroviral medication on time and according to dietary instructions. Patients who reported deviation from their regimen showed lower drug exposure compared with fully adherent patients (median concentration ratio, 0.81 vs 1.07; P =.001). Among those receiving HAART for at least 24 weeks, patients reporting deviation from their regimen were less likely to have plasma HIV-1 RNA levels below 500 copies/mL (adjusted odds ratio, 4.0; 95% confidence interval, 1.4-11.6) compared with fully adherent patients. CONCLUSIONS: Only half of the patients took all antiretroviral medication in accordance with time and dietary instructions in the preceding week. Deviation from the antiretroviral regimen was associated with decreased drug exposure and a decreased likelihood of having suppressed plasma HIV-1 RNA loads. Patient adherence should remain a prime concern in the management of HIV-1 infection.

Steady-state pharmacokinetics of twice-daily dosing of saquinavir plus ritonavir in HIV-1-infected individuals.

OBJECTIVE: To compare the steady state plasma pharmacokinetics of 1000 mg of saquinavir (SQV) in a soft-gel capsule (SGC) formulation in combination with 100 mg of ritonavir (RTV) (capsules) in a twice-daily dosing regimen in HIV-1-infected individuals with historical controls who used 400 mg of SQV in a hard-gel capsule (HGC) formulation in combination with 400 mg of RTV and to investigate the plasma pharmacokinetics of the 1000 mg/100 mg regimen after normal and high-fat breakfasts. DESIGN: Open-label, crossover, steady-state pharmacokinetic study. METHODS: Six HIV-1-infected individuals who used either 1200 mg of SQV (SGC or HGC) three times daily or 400 mg twice daily in combination with 400 mg of RTV twice daily were included. Each patient was switched to 1000 mg of SQV SGC twice daily in combination with 100 mg of RTV twice daily. After 14 days, the patients came to the hospital for assessment of a pharmacokinetic profile during 12 hours. Patients were randomized to receive a high-fat (+/-45 g of fat) or normal (+/-20 g of fat) breakfast. After 7 days, a second pharmacokinetic profile was assessed after ingestion of the drugs with the alternate breakfast. A noncompartmental pharmacokinetic method was used to calculate the area under the plasma concentration versus time curve (AUC0-12h), the maximum plasma concentration (Cmax), the plasma trough concentration (C12h), and the elimination half-life in plasma (t1/2). The obtained pharmacokinetic parameters were compared with those of 12 patients using SQV HGC (400 mg twice daily) in combination with RTV (400 mg twice daily). RESULTS: The median values of the pharmacokinetic parameters for SQV SGC (1000 mg twice daily, normal breakfast) were: AUC0-12h, 18.84 h*mg/L; Cmax, 3.66 mg/L; C12h, 0.40 mg/L; and t1/2, 3.0 hours. The median values of the pharmacokinetic parameters for SQV HGC (400 mg twice daily, normal breakfast) were: AUC0-12h, 6.99 h*mg/L; Cmax, 1.28 mg/L; C12h, 0.23 mg/L; and t1/2, 3.9 hours. The exposure to SQV in the dosing regimen of 1000 mg twice daily in combination with 100 mg of RTV twice daily was significantly higher than the exposure to SQV in a dosing regimen of 400 mg twice daily in combination with 400 mg of RTV twice daily. The pharmacokinetic parameters of SQV SGC in the dosing regimen of 1000 mg twice daily in combination with 100 mg of RTV twice daily were not significantly different after ingestion of a high-fat or normal breakfast (p >.35). CONCLUSIONS: The combination of 1000 mg of SQV SGC twice daily and 100 mg of RTV twice daily resulted in a higher exposure to SQV compared with the exposure to SQV obtained when SQV is used in the 400 mg/400 mg twice-daily combination with RTV. In this small number of patients, no significant differences in exposure were seen after ingestion of either a normal or high-fat breakfast. From a pharmacokinetic perspective, the combination of 1000 mg of SQV SGC twice daily and 100 mg of RTV twice daily seems to be a good option for further clinical evaluation.

The effect of fluconazole on ritonavir and saquinavir pharmacokinetics in HIV-1-infected individuals.

AIMS: To study the effect of fluconazole on the steady-state pharmacokinetics of the protease inhibitors ritonavir and saquinavir in HIV-1-infected patients. METHODS: Five subjects treated with saquinavir and three with ritonavir received the protease inhibitor alone (saquinavir 1200 mg three times daily, ritonavir 600 mg twice daily) on day 1, and the same protease inhibitor in combination with fluconazole (400 mg on day 2 and 200 mg on days 3 to 8). Pharmacokinetic parameters were determined on days 1 and 8. RESULTS: In the saquinavir group, the median increase in the area under the plasma concentration vs time curve was 50% from 1800 microg l(-1) h to 2700 microg l(-1) h (P = 0.04, median increase: 900 microg l(-1) h; 2.5 and 97.5 percentile: 500-1300), and 56% for the peak concentration in plasma (from 550 to 870 microg l(-1), P = 0.04; median increase: 320 microg l(-1) h, 2.5 and 97.5 percentile: 60-450 microg l(-1)). In the ritonavir group, there were no detectable changes in the pharmacokinetic parameters on addition of fluconazole. CONCLUSIONS: Because of the favourable safety profile of saquinavir, dose adjustments are probably not necessary with concomitant use of fluconazole, as is the case for ritonavir.

Saliva as an alternative body fluid for therapeutic drug monitoring of the nonnucleoside reverse transcription inhibitor nevirapine.

The objective of this study was to evaluate the applicability of saliva as an alternative body fluid for therapeutic drug monitoring of nevirapine. The pharmacokinetics of nevirapine in plasma and saliva during a dosing interval was assessed in HIV-1-infected patients taking nevirapine (200 mg twice daily) to explore the relation between the concentration of nevirapine in plasma and saliva. To validate the anticipated relationship prospectively, single, paired plasma and saliva samples were obtained from nevirapine-treated HIV-1-infected outpatients. The plasma nevirapine concentration was strongly correlated with the salivary concentration. The mean saliva/plasma concentration ratio was 0.51 and was independent of the time after ingestion. Salivary nevirapine concentrations were used to estimate the corresponding plasma concentrations for 31 outpatients. Compared with the true plasma concentrations, the estimated concentrations were biased by -4.2%, with a precision of 13.3%. These data show a strong correlation between the salivary and plasma concentrations of nevirapine at a dosage of 200 mg twice daily. This relation has been validated prospectively, and the prediction of plasma concentrations was accurate and precise. Therefore, the authors conclude that saliva can be a useful body fluid for therapeutic drug monitoring of nevirapine.

A retrospective, cohort-based survey of patients using twice-daily indinavir + ritonavir combinations: pharmacokinetics, safety, and efficacy.

OBJECTIVE: To describe the pharmacokinetics, safety, and efficacy of twice-daily indinavir + ritonavir regimens DESIGN: A cohort-based survey of HIV-infected patients who either used indinavir 800 mg + ritonavir 100 mg twice daily or indinavir 400 mg + ritonavir 400 mg twice daily. METHODS: Data were extracted from a database of samples sent to our laboratory for measurement of indinavir + ritonavir plasma concentrations. Patient characteristics, safety, and efficacy measurements were collected by retrospective chart review. RESULTS: 100 Patients using 800-mg indinavir + 100-mg ritonavir twice daily and 32 patients using 400-mg indinavir + 400-mg ritonavir twice daily were eligible. Median peak and trough concentrations of indinavir were 6.8 and 0.77 mg/L in the 800/100 group and 2.6 and 0.45 mg/L in the 400/400 group. The most frequently found side effects were nausea and vomiting, which occurred in 22.1% and 34.9% of the patients in the 800/100 and the 400/400 groups, respectively. Viral load data were analyzed for patients who switched from 800-mg indinavir three times daily to one of the indinavir + ritonavir twice daily regimens. At the time of switch 63% (800/100 group) and 60% (400/400 group) had an undetectable viral load and this increased to 77% and 70%, respectively, during follow-up. Patients who switched to the 400/400 group discontinued treatment more frequently than patients who switched to the 800/100 group (70% vs. 26%, p =.008). CONCLUSIONS: Indinavir + ritonavir regimens show improved pharmacokinetic properties, allowing twice-daily dosing with food. Clinical data suggest that safety and efficacy is at least as good as with indinavir three-times-daily regimens without ritonavir. Prospective, comparative trials are needed to properly assess the role in HIV therapy of these twice-daily indinavir + ritonavir regimens.

Limited sampling strategies for the estimation of the systemic exposure to the HIV-1 nonnucleoside reverse transcriptase inhibitor nevirapine.

The objective of this study was to develop and validate a limited sampling strategy (LSS) that allows accurate and precise estimation of the area under the plasma concentration versus time curve (AUC) of nevirapine, when used in the licensed dosage of 200 mg twice daily. Because nevirapine has a long plasma elimination half-life and the plasma concentration shows little variation within the 12-hour dosing interval, the authors also wanted to explore whether a time frame exists for which a single-sample LSS can be applied. Twenty HIV-1-infected individuals receiving steady-state treatment with nevirapine (200 mg twice daily) were enrolled. For the development of the LSS, 10 patients were randomly selected from the study population (index set). The pharmacokinetic results from the other 10 patients (validation set) were used for prospective validation of the proposed LSS. Blood samples were obtained before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after ingestion. The relationship between the nevirapine concentration at each of the designated time points and the AUC 12h was evaluated by univariate and multivariate linear regression analysis. At each of the sampling times, a strong correlation was observed between the nevirapine concentration and the corresponding AUC 12h (r > 0.97). This allows for a single-sample LSS, using any time point during the dosing interval. When a single equation is preferred, the concentration of nevirapine in a random sample drawn 2 to 4 hours after ingestion of nevirapine (C 2-4h; in microg/mL) can be used for accurate estimation of the AUC 12h (in h x microg/mL) by using the equation AUC 12h (h x microg/mL) = 11.699 (h) x C 2-4h (microg/mL) - 4.381 (h x microg/mL). Validation of this equation resulted in a predicted AUC 12h that was nonbiased and very precise. These data show that the nevirapine concentration at each time point during the dosing interval can be used for accurate estimation of the AUC 12h. Even more practical, a sample obtained at any time between 2 and 4 hours after ingestion of nevirapine can be used. The authors therefore conclude that less intensive sampling (i.e., a single sample) can readily be used to assess the AUC 12h of nevirapine when used in a dosage of 200 mg twice daily.

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.

Saliva as a specimen for monitoring compliance but not for predicting plasma concentrations in patients with HIV treated with indinavir.

The presence of the HIV-protease inhibitor indinavir in saliva was analyzed to investigate whether salivary indinavir concentrations are applicable to monitor compliance and/or predict plasma indinavir levels. Fourteen HIV-infected outpatients treated with indinavir and 24 healthy volunteers who ingested a single dose of indinavir were included. Paired plasma and citric-acid-stimulated saliva samples were analyzed by high-performance liquid chromatography (HPLC). Stimulated salivary indinavir concentrations showed a high correlation (r = 0.85, p < 0.01) with corresponding plasma levels. The median saliva/plasma ratio was 65% (P25 50%; P75 94%). The ratios were independent of the plasma concentration; however, a relation with time after ingestion was seen. The unbound fraction of indinavir in plasma was not significantly correlated with the saliva/plasma ratio after stimulated saliva collection, in contrast with a subset of nonstimulated saliva from healthy volunteers, where we did find a significant correlation. Although stimulated salivary indinavir concentrations are highly correlated with plasma concentrations, it is not possible to predict plasma indinavir levels by the salivary concentrations for purposes of therapeutic drug monitoring, due to large interindividual and intraindividual variation. Nevertheless, monitoring compliance by measuring the presence of indinavir in saliva is possible: ingestion of indinavir can be assessed with a sensitivity of 84.8% in the whole dosing interval or with 98.8% between 1 and 6 hours after the last dose, which is comparable with plasma.

Once-daily dosing of saquinavir and low-dose ritonavir in HIV-1-infected individuals: a pharmacokinetic pilot study.

OBJECTIVE: To investigate the steady-state pharmacokinetics of a once-daily dosing regimen of saquinavir soft gelatin capsules in combination with a low dose of ritonavir in HIV-1-infected individuals. DESIGN: Open-label, multi-dose, pharmacokinetic pilot study. PATIENTS: Seven HIV-1-infected individuals who were treated with saquinavir hard gelatin capsules 400 mg twice daily + ritonavir liquid formulation 400 mg twice daily were switched to saquinavir soft gelatin formulation 1600 mg once daily in combination with ritonavir liquid formulation 200 mg once daily (day 0). Patients were instructed to ingest saquinavir and ritonavir simultaneously in the morning and with a meal. METHODS: Steady-state pharmacokinetics of saquinavir and ritonavir were assessed during a 24 h dosing interval after 2 weeks of continued therapy (day 14). Plasma saquinavir and ritonavir concentrations were measured using a validated high performance liquid chromatography assay. In addition, plasma HIV-1 RNA, and fasting total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels were measured on days 0 and 14. A non-compartmental pharmacokinetic method was used to calculate the area under the plasma concentration versus time curve (AUC[0-24h]), the maximum and trough plasma concentrations (Cmax and Cmin), the time to reach Cmax (Tmax), the elimination half-life (t1/2), the apparent clearance (Cl/F), and the apparent volume of distribution (V/F). RESULTS: Median (range) values of the pharmacokinetic parameters for saquinavir after 2 weeks of treatment were: AUC[0-24h], 19,802h* ng/ml (3720-74,016); Cmax, 2936 ng/ml (573-6848); Cmin, 84 ng/ml (11-854); Tmax, 3.5 h (3.0-4.0), t1/2, 6.8 h (4.6-10.2); Cl/F, 81 l/h (22-430); V/F, 1189 l (215-3086). Ritonavir concentrations were always below the 90% effective concentration of 2100 ng/ml (median Cmax, 1323 ng/ml; range, 692-1528 ng/ml). No significant changes were observed for total serum cholesterol, high-density lipoprotein, and low-density lipoprotein levels between days 0 and 14 (P > or = 0.24). In six out of seven patients the fasting serum triglyceride levels were lower 2 weeks after the treatment switch (median decrease was 32%, P = 0.03). No significant changes in plasma HIV-1 RNA concentrations were observed between days 0 and 14. The regimen was generally well tolerated. CONCLUSIONS: This pharmacokinetic study indicates that the combination of 1600 mg of saquinavir (soft gelatin capsules) and 200 mg of ritonavir (liquid formulation) in a once-daily dosing regimen generally results in therapeutic plasma concentrations of saquinavir. Due to the large interindividual variation in saquinavir exposure, the monitoring of saquinavir concentrations in plasma is warranted. These pharmacokinetic findings rationalize the further clinical evaluation of once-daily dosing of this combination of protease inhibitors.

The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1-infected individuals.

OBJECTIVE: To investigate and to compare the steady-state plasma pharmacokinetics of nevirapine in a dosing regimen of 400 mg once daily versus 200 mg twice daily in HIV-1-infected individuals. DESIGN: Open-label, randomized, cross-over study. METHODS: Twenty HIV-1-infected individuals who already used nevirapine as part of their antiretroviral regimen were randomized to continue their current regimen (200 mg twice daily) or to switch to the alternate regimen (400 mg once daily). The steady-state plasma pharmacokinetics of nevirapine were assessed after 2 weeks during a 24-h period. Subsequently, patients were switched to the alternate regimen and the pharmacokinetics of nevirapine were assessed again after 2 weeks. Non-compartmental methods were used to calculate the area under the plasma concentration versus time curve (AUC[24h]), and the maximal (Cmax) and minimal plasma concentration (Cmin), the time to Cmax (t(max)), the plasma elimination half-life (t1/2), the apparent oral clearance (Cl/F) and the apparent volume of distribution (V/F). Differences in these pharmacokinetic parameters for the two dosing regimens were tested using ANOVA. RESULTS: The exposure to nevirapine, as measured by the AUC[24h], was not significantly different between the 400 mg once daily and 200 mg twice daily dosing regimen (P = 0.60). Furthermore, the values for t(max), t1/2 Cl/F and V/F were not significantly different between the two dosing regimens (P > or = 0.08). However, Cmax and Cmin were higher and lower, respectively, when nevirapine was used in the once daily regimen as compared with the twice daily regimen. The median values for Cmax and Cmin as measured for the once daily and twice daily regimens were 6.69 and 5.74 microg/ml, respectively (P = 0.03), and 2.88 and 3.73 microg/ml, respectively (P < 0.01). CONCLUSION: These data show that the daily exposure to nevirapine, as measured by the plasma AUC[24h], is not different between a 400 mg once daily and a 200 mg twice daily dosing regimen. However, Cmax and Cmin are higher and lower, respectively, for the once daily regimen as compared with the twice daily regimen. The clinical implications of these differences remain to be established.