Lopinavir/ritonavir pharmacokinetics, efficacy, and safety in HIV and hepatitis B or C coinfected adults without symptoms of hepatic impairment.

OBJECTIVE: Lopinavir/ritonavir plus nucleoside reverse transcriptase inhibitors is one standard antiretroviral therapy regimen, both in patients with HIV alone and coinfected with hepatitis B or C. Our objective was to investigate whether hepatitis coinfection without clinical signs of hepatic impairment is a cofactor altering lopinavir pharmacokinetics and influencing therapy outcome. METHODS: Steady-state 12-hour pharmacokinetic profiles of lopinavir/ritonavir were assessed in patients with (group 1, n = 20) or without (group 2, n = 36) hepatitis coinfection, taking lopinavir/ritonavir 400/100 mg twice a day plus nucleoside reverse transcriptase inhibitors, measured by means of high-performance liquid chromatography-tandem mass spectrometry. Demographic (sex, age, weight), pharmacological (formulation, comedication), clinical, and virological/immunologic parameters (HIV-RNA PCR, CD4(+) cell count) were compared between the groups and included in regression analyses for correlations with lopinavir pharmacokinetic parameters (C(min), C(max), AUC, CL, and t(1/2)) and viral load evolution over 48 weeks on therapy. Patient pairs were matched 1:2 for the parameters sex, age, weight, ethnicity, and drug formulation. RESULTS: None of the hepatitis-related cofactors (aspartate aminotransferase, alanine aminotransferase, γGT, HBe Ag, HBsAg, HCV-RNA PCR, HCV-therapy) had an influence on lopinavir pharmacokinetics in this group of patients. Lopinavir C(min) (P = 0.039) and area under the curve (P = 0.038) and ritonavir C(max) (P = 0.049) were significantly enhanced in hepatitis-coinfected patients, but correlated only with drug formulation (ie, soft gel capsule or Meltrex tablet formulation, multivariate regression analysis, P = 0.001), not hepatitis coinfection. CONCLUSIONS: Despite moderately enhanced lopinavir/ritonavir plasma concentrations, regular therapeutic drug monitoring is not to be considered in hepatitis-coinfected patients without hepatic impairment. Antiviral efficacy is comparable between both groups, a less-pronounced CD4(+) cell increase in hepatitis-coinfected patients is in line with previously published data.

Pharmacokinetics and pharmacodynamics of etravirine 400 mg once daily in treatment-naïve patients.

BACKGROUND: Etravirine is currently approved for HIV treatment-experienced patients at a dose of 200 mg twice daily. The long terminal elimination half-life of etravirine should support once-daily dosing. METHODS: In the double-blind 48-week SENSE trial, 157 antiretroviral treatment-naïve patients were randomly assigned to receive etravirine 400 mg once daily (n = 79) or efavirenz 600 mg once daily (n = 78), plus 2 nucleoside reverse transcriptase inhibitors (NRTIs). Sparse sampling for etravirine plasma concentrations was conducted during the 48-week trial. Area under the curve over the dosing interval (AUC24h) and trough concentration (C0h) were estimated using a population pharmacokinetic model and compared with previous results using the 200-mg twice-daily dosage. The relationship between etravirine AUC24h and C0h with efficacy and safety was also assessed. RESULTS: By week 48, the percentage of patients in the etravirine arm with HIV RNA <50 copies/ mL was 75.9% in the intent-to-treat switch equals failure analysis and 92.3% in the on-treatment analysis; no patient developed genotypic or phenotypic resistance to NRTIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs) after virologic failure. Seventy-one subjects had evaluable etravirine pharmacokinetics. The median (interquartile range) of etravirine AUC24h and C0h were 12,447 (8,261-15,652) ng•h/mL and 330 (188-472) ng/mL, respectively. There was no correlation between etravirine exposure and virologic response or adverse events. CONCLUSIONS: In the SENSE trial, etravirine 400 mg once daily achieved similar exposures to historical reference data on etravirine when dosed at 200 mg twice daily. There was no apparent relationship between the pharmacokinetics of etravirine and virologic response or adverse events.

Daily dosing of tacrolimus in patients treated with HIV-1 therapy containing a ritonavir-boosted protease inhibitor or raltegravir.

OBJECTIVES: The number of HIV-infected patients receiving orthotopic liver transplantation (OLTX) is increasing. One major challenge is the severe drug-drug interactions between immunosuppressive drugs such as tacrolimus and ritonavir-boosted HIV-1 protease inhibitors (PIs). The introduction of raltegravir, which is not metabolized by the cytochrome system, may allow concomitant treatment without dose adaptation. PATIENTS AND METHODS: We conducted a retrospective analysis of HIV-1-infected patients receiving tacrolimus concomitantly with different HIV therapies, including 12 h pharmacokinetic assessment of drug levels. RESULTS: Three OLTX patients received a ritonavir-boosted PI therapy when tacrolimus was added at very low doses of 0.06, 0.03 and 0.08 mg daily. Median tacrolimus blood levels were 6.6, 3.0 and 7.9 ng/mL over a follow-up period of 8, 22 and 33 months, respectively. In two other patients (one after OLTX and one with Crohn's disease), a raltegravir-based HIV therapy was started while patients received 1 or 2 mg of tacrolimus twice daily. No tacrolimus dose adjustment was necessary and drug levels remained unchanged. CONCLUSIONS: Decreasing the dose of tacrolimus to 0.03-0.08 mg daily in patients with concomitant boosted PI therapy resulted in stable tacrolimus blood levels without alteration of PI drug levels. Concomitant use of raltegravir and tacrolimus revealed no clinically relevant drug interaction.

Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting.

OBJECTIVE: The human immundeficiency virus (HIV) protease inhibitor atazanavir is often used in once-daily observed therapy of methadone substituted former opiate drug users. We performed a matched-pairs analysis on 24 patients (12 men/women) taking atazanavir/ritonavir 300/100 mg daily plus reverse transcriptase inhibitors, with (n = 12) or without (n = 12) methadone co-administration. METHODS: Twenty-four-hour pharmacokinetic profiles of atazanavir/ritonavir were assessed at steady-state and measured by liquid chromatography-tandem mass spectrometry. The geometric mean (GM, t test) minimum and maximum plasma drug concentrations (C(min), C(max)), area under the concentration-time curve (AUC), and total clearance (CL(total)) were compared between the groups of pairs, which were matched for age, sex, weight, and ethnicity. RESULTS: The GM [90% confidence interval (CI)] of the atazanavir C(min), C(max), and AUC of patients taking the methadone oral solution at doses of 20-175 mg/day simultaneously with antiretroviral therapy were impaired compared to patients not taking methadone oral solution: C(min) = 315 (range 197-448) vs. 519 (279-793) ng/mL [GM ratio (GMR) = 0.61, p = 0.229]; C(max) = 1714 (1238-2262) vs. 3190 (2412-4076) ng/mL (GMR = 0.54, p = 0.018); AUC = 21,987 (15,870-29,327) vs. 35,572 (26,211-46,728) ng h/mL (GMR = 0.62, p = 0.074). Methadone dose, which is proportional to the amount of methadone oral solution (10 mg/mL), was significantly correlated to atazanavir C(max) (r (2) = 0.40, p = 0.001) and AUC (r (2) = 0.32, p = 0.006). Ritonavir pharmacokinetics was similar between the groups with C(min), C(max), and AUC GMR of 1.01, 0.80, and 0.96, respectively. CONCLUSION: The partial decrease in atazanavir plasma concentrations in patients concomitantly taking racemic methadone oral solution in this daily observed therapy setting deserves further attention, and therapeutic drug monitoring should be considered.

Persistence of nevirapine in breast milk and plasma of mothers and their children after single-dose administration.

OBJECTIVES: Nevirapine is widely used in the developing world for the prevention of mother-to-child transmission (PMTCT) of HIV. A single mutation in the HIV genome is sufficient to lead to significant nevirapine resistance. Persistence of low-level drug concentrations in body compartments can foster resistance formation. In this study, concentration-time courses of nevirapine after single-dose administration were analysed over an extended post-partum period. PATIENTS AND METHODS: Breast milk and plasma samples of 62 HIV-positive Ugandan mother-child pairs who had received single-dose nevirapine were collected at delivery and 1, 2 and 6 weeks post-partum. Nevirapine concentrations were quantified by LC/tandem-mass-spectrometry using a quantification limit of 15 ng/mL, and a population pharmacokinetic (PK) analysis was performed. RESULTS: Concentration-time profiles in breast milk, maternal plasma and child plasma showed similar shapes. At week 1, median nevirapine concentrations were 164 ng/mL in maternal plasma, 114 ng/mL in breast milk and 183 ng/mL in child plasma. The population PK model predicted nevirapine concentrations>10 ng/mL (IC50 for nevirapine) for 13 days in breast milk, 14 days in maternal plasma and 18 days in child plasma in 80% of the samples. CONCLUSIONS: Nevirapine concentrations were present for 2-3 weeks in the three compartments. The concentrations are probably sufficiently high to protect most breastfed children from HIV transmission during the first 2 weeks. The long presence of slowly decreasing levels of nevirapine is likely to induce resistance formation. Post-natal addition of antiretrovirals for 1 week only, as recommended in the current PMTCT guidelines, will not suffice to avoid nevirapine resistance formation.

Pharmacokinetics, safety and efficacy of saquinavir/ ritonavir 1,000/100 mg twice daily as HIV type-1 therapy and transmission prophylaxis in pregnancy.

BACKGROUND: A saquinavir/ritonavir-containing regimen is one option for the prevention of mother-to-child transmission of HIV during pregnancy. We evaluated the pharmacokinetics, efficacy and safety of saquinavir/ritonavir 1,000/100 mg twice daily plus nucleos(t)ide reverse transcriptase inhibitors in 13 women during late pregnancy and compared the results to those of 15 non-pregnant women. METHODS: Protease inhibitor plasma concentration profiles were assessed at 12 h using a standardized therapeutic drug monitoring procedure and measured by LC-MS/MS. Minimum and maximum concentrations (C(min) and C(max)), area under the plasma concentration-time curve (AUC(0-12 h)), and total clearance (CL(total)) were compared between the groups and correlated to demographic, physiological and clinical cofactors. Antiviral and immunological efficacy and safety were investigated. RESULTS: The geometric means (90% confidence interval [CI]) for saquinavir C(min), C(max) and AUC(0-2 h) of pregnant versus non-pregnant women were 572 (437-717) versus 765 (485-1,052, P = 0.064) ng/ml, 2,168 (1,594-2,807) versus 3,344 (2,429-4,350; P = 0.045) ng/ml and 15,512 (11,657-19,943) versus 24,027 (17,454-31,548, P = 0.029) ng x h/ml. The geometric means (90% CI) for ritonavir C(min), C(max) and AUC(0+12 h) were 190 (148-234) versus 310 (240-381, P = 0.011) ng/ml, 781 (580-999) versus 1,552 (1,127-2,007, P = 0.004) ng/ml and 5,576 (4,303-7,006) versus 10,528 (8,131-13,177, P = 0.003) ng x h/ml. Age, weight, saquinavir dose per weight and body mass index differed significantly; saquinavir C(min) and AUC(0-12 h) were correlated with ritonavir C(min) and saquinavir dose per weight. After a mean of 11 weeks treatment, 12 of 13 pregnant women had a viral load < 400 copies/ml, which was similar to the results of non-pregnant women. CONCLUSIONS: Although saquinavir plasma concentrations were significantly lower in pregnant women compared with non-pregnant women, all pregnant women displayed a saquinavir AUC(0-12 h) > 10,000 ng x h/ml, 92.3% had a viral load < 400 copies/ml at birth. Saquinavir was well tolerated by the mothers and all newborn children were HIV type-1 negative at 18 months of age.

Fosamprenavir/ritonavir plus tenofovir does not affect amprenavir pharmacokinetics: no effect of tenofovir.

The effect of tenofovir disoproxil fumarate (TDF) in combination with two boosted fosamprenavir regimens on amprenavir pharmacokinetic parameters was assessed in this prospective phase I crossover study with 30 healthy volunteers. The co-administration of TDF 300 mg once a day with fosamprenavir/ritonavir 1400/200 mg or 1400/100 mg once a day has no effect on the pharmacokinetics of amprenavir and results in non-significant increases of ritonavir pharmacokinetic parameters, suggesting that no dose modification is necessary when combining fosamprenavir/ritonavir with TDF.

Placental transfer and pharmacokinetics of lopinavir and other protease inhibitors in combination with nevirapine at delivery.

BACKGROUND: Antiretroviral combination therapies, including nevirapine (NVP) and protease inhibitors (PI), are increasingly used in the treatment and for the prophylaxis of vertical HIV-1 transmission in HIV-1 infected pregnant women. OBJECTIVE: To determine pharmacokinetics and placental transfer of NVP and different PI in pregnancy we measured drug levels in maternal and foetal compartments at the day of delivery. DESIGN AND METHODS: We conducted a prospective study in 40 eligible HIV-1 infected pregnant women who gave birth in our hospital. A pre-dose to 6 h post-dose steady-state pharmacokinetic analysis (n = 35) of the drugs on the day of the scheduled Caesarean section was performed. In addition cord blood and amniotic fluid drug levels were measured (n = 40). RESULTS: In all women NVP plasma concentrations (n = 20) were below the recommended level. PI plasma concentrations (nelfinavir, n = 5; saquinavir, n = 3; lopinavir, n = 10; ritonavir, n = 13) were extremely variable. Cord blood and amniotic fluid drug levels suggested that NVP passes the placenta unrestricted whereas PI were detected in smaller concentrations in the foetal compartment. CONCLUSIONS: Because of the changed pharmacokinetics of antiretroviral drugs in pregnancy therapeutic drug monitoring could be important and dose adjustment should be considered. The minimal placental transfer of PI is desirable from the perspective that the foetus is protected from potentially teratogenic agents. However, it is not known if antiretroviral compounds in the foetal compartment contribute to the risk reduction of vertical HIV-1 transmission, and whether the property of missing placental transfer is in fact beneficial for the newborn.

Therapeutic drug monitoring and drug-drug interactions involving antiretroviral drugs.

The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pls) provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM. In April 2004, a panel of experts met for the second time in Rome, Italy. This was following the inaugural meeting in Perugia, Italy, in October 2000, which resulted in the manuscript published in AIDS 2002, 16(Suppl 1):S5-S37. The objectives of this second meeting were to review and update the numerous questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals. A major focus of the meeting was to discuss and critically analyse recent and precedent clinical drug-drug interaction data to provide a clear framework of the pharmacological basis of how one drug may impact the disposition of another. This report, which has been updated to include material published or presented at international conferences up to the end of December 2004, reviews recent pivotal pharmacokinetic interaction data and provides advice to clinical care providers on how some drug-drug interactions may be prevented, avoided or managed, and, when data are available, on what dose adjustments and interventions should be performed.

The steady-state pharmacokinetics of nelfinavir in combination with tenofovir in HIV-infected patients.

BACKGROUND: The nucleotide analogue, tenofovir, has been shown to lower plasma atazanavir levels in pharmacokinetic trials, an interaction that may be partly reversed by the addition of ritonavir, whereas plasma tenofovir levels are themselves raised when the drug is combined with lopinavir/ritonavir. OBJECTIVE: To investigate the effect of tenofovir coadministration on the steady-state pharmacokinetics of nelfinavir in HIV-infected patients. METHODS: Eighteen patients received nelfinavir 1250 mg twice daily plus prescribed nucleoside reverse transcriptase inhibitors for at least 14 days, with pharmacokinetic measurements performed on day 15. Treatment with nelfinavir was continued for another 7 days with the addition of 300 mg tenofovir once daily. Pharmacokinetic measurements were repeated on day 22. Plasma samples were analysed by liquid chromatography-tandem mass spectrometry for nelfinavir, its primary metabolite, M8, and tenofovir. The parameters AUC0-12, C0, Cmax and Tmax were compared for nelfinavir with and without tenofovir by calculating geometric mean ratios (GMRs) of the pharmacokinetic parameters with associated 95% confidence intervals (95% CIs). Safety was assessed throughout the study. RESULTS: The addition of tenofovir to the nelfinavir-based regimen had no effect on the pharmacokinetics of nelfinavir. The GMR of the nelfinavir AUC0-12 values was 0.97 (95% CI: 0.80-1.17). There was a slight decrease in M8 metabolite (AUC0-12 ratio, 0.87; 95% CI: 0.68-1.11) but this was not significant. No serious adverse events occurred through the study period. CONCLUSION: Nelfinavir does not require dose adjustment when coadministered with tenofovir and appears to be well-tolerated by HIV-infected patients.

Current status and future prospects of therapeutic drug monitoring and applied clinical pharmacology in antiretroviral therapy.

The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors and protease inhibitors provide a framework for the implementation of TDM in certain defined scenarios in clinical practice. However, the utility of TDM is considered to be on an individual basis until more data are obtained from large clinical trials showing the benefit of TDM. In April 2004, a panel of experts met in Rome, Italy. This followed an inaugural meeting in Perugia, Italy, in October 2000, which resulted in the article published in AIDS 2002, 16(Suppl 1):S5-S37. The objectives of this second meeting were to review the questions surrounding TDM of antiretroviral drugs and discuss the clinical utility, current concerns and future prospects of drug concentration monitoring in the care of HIV-1-infected individuals. This report, which has been updated to include material published or presented at international conferences up to the end of September 2004, reviews pharmacokinetic and pharmacodynamic data and reports the issues discussed by the panel, offering advice to clinical care providers who may be currently, or are considering incorporating TDM into the routine care of their patients. In addition, the panel formulated a series of position statements that are relevant to the interpretation of current data and can aid the design of future clinical trials.

Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen.

OBJECTIVE: To determine the pharmacokinetics of saquinavir hard-gel capsules/ritonavir/atazanavir co-administered once daily at 1600/100/300 mg in HIV-infected individuals. METHODS: Eighteen patients receiving saquinavir/ritonavir switched to 1600/100 mg once daily a minimum of 3 days before the study. On study day 1, levels of saquinavir and ritonavir were determined over 24 h. Atazanavir (300 mg once daily) was then added to the regimen. On day 11, a pharmacokinetic analysis was performed. Atazanavir was discontinued on day 32. Drug concentrations were measured by high-pressure liquid chromatography-tandem mass spectrometry. Geometric mean ratios (GMR) and 95% confidence intervals (CI) were used to compare saquinavir and ritonavir pharmacokinetic parameters, with and without atazanavir. A safety analysis was performed at screening, days 1, 11, 32 and follow-up. RESULTS: After the addition of atazanavir, statistically significant increases in saquinavir trough plasma concentration (Ctrough GMR, 95% CI 2.12, 1.72-3.50), maximum plasma concentration (Cmax 1.42, 1.24-1.94), area under the plasma concentration-time curve from 0-24 h (AUC0-24 1.60, 1.35-2.43) and ritonavir Cmax (1.58, 1.32-2.08), AUC0-24 (1.41, 1.22-1.74) were observed. The pharmacokinetics of atazanavir compared with those obtained in patients receiving atazanavir/ritonavir without saquinavir. Four patients developed scleral icterus and two jaundice. Total and unconjugated bilirubin increased approximately fivefold during atazanavir therapy. CONCLUSION: The addition of atazanavir to saquinavir/ritonavir increased saquinavir Ctrough, Cmax and AUC0-24 by 112, 42 and 60%. Ritonavir Cmax and AUCo-24 increased by 34 and 41%. The regimen was well tolerated, with no significant change in laboratory parameters, except for the occurrence of hyperbilirubinemia.

Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/ritonavir.

OBJECTIVE: To assess the pharmacokinetic interaction of saquinavir and lopinavir/ritonavir. DESIGN: Patients from the Frankfurt HIV cohort with limited reverse transcriptase inhibitor (RTI) options received the protease inhibitor (PI) combination of saquinavir (soft-gel capsules, 1000 mg twice a day) plus lopinavir/ritonavir (400/100 mg twice a day), without RTI (LOPSAQ group). A control group received the same doses of saquinavir and ritonavir plus two to three RTI (RITSAQ group). A steady-state 12 h pharmacokinetic assessment was performed. METHODS: Plasma levels of saquinavir, ritonavir and lopinavir were determined by liquid chromatography-tandem mass spectrophotometry. Minimum and maximum plasma concentrations (Cmin and Cmax), the clearance (Cltot) and the area under the concentration time curve (AUC) were calculated. RESULTS: Data were collected from 45 patients (LOPSAQ) and 32 patients (RITSAQ). There was no significant difference between the groups for median saquinavir Cmin, Cmax, Cltot and AUC (LOPSAQ: 543 ng/ml, 2300 ng/ml, 1020 ml/min and 16 977 ng*h/ml; RITSAQ: 427 ng/ml, 2410 ng/ml, 1105 ml/min and 15 130 ng*h/ml). Median ritonavir Cmin, Cmax and AUC were lower, the Cltot was higher in the LOPSAQ group (78 ng/ml, 428 ng/ml and 2972 ng*h/ml, 551 ml/min) compared with RITSAQ (194 ng/ml, 683 ng/ml and 6506 ng*h/ml, 266 ml/min; P < 0.001). Lopinavir levels were similar to historical data. CONCLUSION: Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir. This boosted double PI combination could be an effective option for patients with limited RTI options.

Therapeutic drug monitoring in HIV infection: current status and future directions.

BACKGROUND: Highly active antiretroviral therapy (HAART) can suppress viral replication and prolong patient life substantially. However, HAART can fail for a number of reasons, including incomplete adherence, pharmacokinetic factors and the emergence of resistance. Because the number of possible antiretroviral combinations is limited, the use of existing treatment options must be optimized. Whether the application of therapeutic drug monitoring (TDM) in routine clinical practice may help with this purpose remains a subject of debate. However, TDM has been introduced in some centres despite the lack of guidelines for optimal use of this test. OBJECTIVE: In October 2000, a panel of experts met in Perugia, Italy, to discuss the key issues surrounding the introduction of TDM into routine clinical practice. The purpose of the meeting was to achieve a consensus among panel members on the following issues: (i) validity of data suggesting the utility of TDM in HAART; (ii) patient categories and clinical settings in which TDM may be of most benefit; (iii) target levels of antiretroviral agents; (iv) influence of covariables on target levels of drugs; (v) blood sampling and dosage adjustment strategies; and (vi) future research steps needed to elucidate issues regarding the applicability of TDM in clinical practice. OUTCOME: This report, which has been updated to include data published or presented at conferences up to the end of August 2001, summarizes the data presented and issues discussed at the meeting. This article will guide the reader through the data and discussions that have allowed the panel to formulate a series of position statements regarding the current status and future applications of TDM in antiretroviral therapy. These statements have been formulated to provide suggestions for the design of future TDM clinical trials, as well as to provide useful points of reflection for centres in which TDM is already in use.

Low-dose ritonavir moderately enhances nelfinavir exposure.

BACKGROUND: The protease inhibitor ritonavir is increasingly administered at subtherapeutic doses in highly active antiretroviral treatment, to utilize its potential for drug interactions and to enhance the plasma concentrations of other concomitantly prescribed protease inhibitors. The addition of low doses of ritonavir to nelfinavir was investigated to describe the extent of pharmacokinetic interaction. METHODS: In this randomized, open-label, one-sequence crossover study, nelfinavir 1250 mg twice a day was dosed for 17 days, followed by 14 days of nelfinavir 1250 mg twice a day plus low doses of ritonavir of either 100 mg or 200 mg orally. Twenty-four healthy volunteers were evaluated for pharmacokinetics of nelfinavir, its metabolite M8, and ritonavir. Plasma concentrations were measured up to 12 hours after morning and evening dosing, respectively, on days 14 and 31. RESULTS: Ritonavir increased the area under the plasma concentration-time curve (AUC) of nelfinavir by 20% (P =.024) and 39% (P =.001) after morning and evening administration, respectively. The AUC of nelfinavir metabolite M8 was increased by 74% and 86% after morning and evening dosing (P <.001 for both). CONCLUSION: During ritonavir combination therapy a clear although minor drug effect on nelfinavir pharmacokinetics was demonstrated but no dose effect was shown.

Limited effect of food composition on the pharmacokinetics of nelfinavir administered twice daily.

UNLABELLED: The objective of the study was to investigate the effect of two different breakfasts on the pharmacokinetics of nelfinavir under steady state conditions. METHODS: Twenty-four healthy male volunteers were evaluated in a 17 days open labeled one sequence crossover study evaluating the effect of a 'light' breakfast (350 kcal) compared to a standard breakfast (800 kcal) on the pharmacokinetics of nelfinavir at steady state during 1250 mg twice daily (BID) administration. RESULTS: After administration with a standard breakfast higher concentrations of nelfinavir were observed during the terminal phase than after administration with a 'light' breakfast. The comparison of the log subset 10 transformed parameters C subset 1-hr-postdose, AUC subset 0-12h, C subset max, and C subset 12 hours, showed that the AUC subset 0-12h was decreased by 13% (P = 0.01) after administration with the 'light' breakfast. Nelfinavir 1250 mg BID was well tolerated. CONCLUSIONS: Although drug intake with a 'light' breakfast' showed a statistically significant decrease for nelfinavir AUC subset 0-12h, this marginal 13% reduction is not considered clinically relevant. No significant effects of the two different breakfasts were found for the remaining three parameters tested C subset 1-hr-postdose, C subset max, and C subset 12 hours.

Intrapartum transmission after mucosal exposure to HIV was not observed with single-dose nevirapine for mother and child.

BACKGROUND: Intrapartum transmission of HIV has been reported to be associated with HIV in oropharyngeal secretions (OPSs) of the child. In this study, we analyze the frequency of intrapartum transmission after mucosal exposure to HIV after administration of single-dose nevirapine. METHODS: Eighty mothers and their children participating in a prevention of mother-to-child transmission of HIV program in Uganda who took a single dose of nevirapine according to the HIVNET012 protocol participated in the study. HIV-1 was quantified by polymerase chain reaction (PCR) in the mothers' and children's plasma, in cervicovaginal secretions (CVSs), and in the children's OPSs. Intrapartum transmission was defined as a positive HIV-1 RNA PCR result at week 1 or 2 after birth and a previously negative PCR result. RESULTS: Ninety-seven percent of children had detectable nevirapine in their OPS (median = 592 ng/mL). Fifty-seven (81%) children had HIV-negative OPSs, and 13 (19%) had HIV-positive OPSs. All children of mothers with HIV-negative CVSs had HIV-negative OPSs. HIV-1 levels of OPSs and CVSs correlated (r = 0.33, P = 0.027). None of the babies with detectable HIV-1 in the OPSs became infected by means of intrapartum transmission. CONCLUSION: Intrapartum HIV infection was not observed after mucosal exposure to HIV-1 after administration of a single dose of nevirapine to the mother and child.

Saquinavir, nelfinavir and M8 pharmacokinetics following combined saquinavir, ritonavir and nelfinavir administration.

OBJECTIVES: This study evaluated the steady-state pharmacokinetic interaction between ritonavir-boosted saquinavir and nelfinavir. METHODS: Open label, multiple-dose, two parallel-groups, single crossover study conducted in 24 HIV-infected patients (12 in each group). Patients in the nelfinavir group added saquinavir/ritonavir, 1000/100 mg twice daily to their ongoing stable treatment regimen consisting of nelfinavir, 1250 mg twice daily and two nucleoside reverse transcriptase inhibitors (NRTIs). Patients in the saquinavir group added nelfinavir, 1250 mg twice daily to their ongoing stable treatment regimen consisting of saquinavir/ritonavir, 1000/100 mg twice daily and two NRTIs. Pharmacokinetic assessments were performed before and 7 days after the start of combined treatment with nelfinavir/saquinavir/ritonavir. Blood samples were collected before and 1, 2, 3, 4, 6, 8, 10 and 12 h after dosing for measurement of nelfinavir, the nelfinavir metabolite M8 and saquinavir using liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: The addition of saquinavir/ritonavir to the nelfinavir-containing regimen resulted in significant increases in the M8 pharmacokinetic parameters AUC(0-12), Cmax and C12; geometric mean ratios (90% confidence intervals) of 2.25 ng.h/mL (1.47-3.44), 1.74 ng/mL (1.25-2.40) and 4.21 ng/mL (2.10-8.47), respectively. The intra-individual changes in nelfinavir and saquinavir concentrations were highly variable. Statistical analysis could not discard a relevant interaction but includes the possibility that some parameters may be halved, others more than doubled. At the same time the analysis failed to show any directed change. CONCLUSIONS: The co-administration of nelfinavir and saquinavir/ritonavir leads to unpredictable changes in concentrations of both drugs. It is unclear whether the increased concentrations of M8 are associated with a clinical benefit.