Placental transfer of the HIV integrase inhibitor dolutegravir in an ex vivo human cotyledon perfusion model.

OBJECTIVES: Data on fetal exposure to antiretroviral agents during pregnancy are important to estimate their potential for prevention of mother-to-child transmission (PMTCT) and possible toxicity. For the recently developed HIV integrase inhibitor dolutegravir, clinical data on fetal disposition are not yet available. Dual perfusion of a single placental lobule (cotyledon) provides a useful ex vivo model to predict the in vivo maternal-to-fetal transfer of this drug. The aim of this study was to estimate the transfer of dolutegravir across the human term placenta, using a dual-perfusion cotyledon model. METHODS: After cannulation of the cotyledons (n = 6), a fetal circulation of 6 mL/min and maternal circulation of 12 mL/min were initiated. The perfusion medium consisted of Krebs-Henseleit buffer (pH = 7.2-7.4) supplemented with 10.1 mM glucose, 30 g/L human serum albumin and 0.5 mL/L heparin 5000IE. Dolutegravir was administered to the maternal circulation (∼ 4.2 mg/L) and analysed by UPLC-MS/MS. RESULTS: After 3 h of perfusion, the mean ± SD fetal-to-maternal (FTM) concentration ratio of dolutegravir was 0.6 ± 0.2 and the mean ± SD concentrations in the maternal and fetal compartments were 2.3 ± 0.4 and 1.3 ± 0.3 mg/L, respectively. CONCLUSIONS: Dolutegravir crosses the blood-placental barrier with a mean FTM concentration ratio of 0.6. Compared with other antiretroviral agents, placental transfer of dolutegravir is moderate to high. These data suggest that dolutegravir holds clinical potential for pre-exposure prophylaxis and consequently PMTCT, but also risk of fetal toxicity.

Raltegravir in HIV-1-Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy.

BACKGROUND: The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women. METHODS: An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated. RESULTS: Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9). CONCLUSIONS: Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women. CLINICAL TRIALS REGISTRATION: NCT00825929.

The Effect of Tamoxifen Dose Increment in Patients With Impaired CYP2D6 Activity.

BACKGROUND: The effect of tamoxifen dose elevation on endoxifen serum concentration was investigated in patients with reduced CYP2D6 activity resulting from genetic variation and/or CYP2D6 inhibitor use. Additionally, baseline differences in endoxifen concentrations between the different CYP2D6 phenotypes were studied. METHODS: Patients, treated with tamoxifen 20 mg once daily (QD) for at least 4 weeks, were classified as phenotypic extensive (EM), intermediate (IM), or poor (PM) metabolizer based on their genotype and comedication. In patients with an IM or PM phenotype, the tamoxifen dose was increased to 40 mg QD for 4 weeks. Tamoxifen, 4-OH-tamoxifen, N-desmethyltamoxifen, and endoxifen serum concentrations were measured at baseline and 4 weeks after the dose increment. Side effects of tamoxifen were assessed using the validated Functional Assessment of Cancer Therapy-Endocrine Symptom subscale (FACT-ESS-19). RESULTS: The median baseline endoxifen concentration differed between EMs (11.4 mcg/L: n = 19), IMs (8.3 mcg/L: n = 16), and PMs (4.0 mcg/L: n = 7), P = 0.040. Tamoxifen dose elevation significantly increased the median endoxifen concentrations in 12 IMs from 9.5 to 17.4 mcg/L (P < 0.001) and in 4 PMs from 3.8 to 7.8 mcg/L (P = 0.001), without influencing median FACT-ESS-19 scores. CONCLUSIONS: Raising the tamoxifen dose to 40 mg QD significantly increased endoxifen concentrations in IMs and PMs without increasing side effects. The tamoxifen dose increment in PMs was insufficient to reach endoxifen concentrations equal to those observed in EMs. Future studies will clarify the direct effect of endoxifen exposure on tamoxifen efficacy and may reveal a threshold endoxifen concentration that is critical for its efficacy.

Lack of a clinically significant drug-drug interaction in healthy volunteers between the hepatitis C virus protease inhibitor boceprevir and the HIV integrase inhibitor raltegravir.

BACKGROUND: Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are likely to use both HIV and HCV treatment. Drug-drug interactions have been demonstrated between boceprevir, an HCV protease inhibitor, and frequently prescribed antiretroviral drugs, such as efavirenz and boosted HIV protease inhibitors. Concomitant administration of boceprevir with these drugs should be avoided. This study was designed to investigate the absence of a drug-drug interaction between boceprevir and raltegravir, an HIV integrase inhibitor. METHODS: This was an open-label, randomized, 2-period, crossover phase 1 trial in 24 healthy volunteers. All subjects were randomly assigned to receive boceprevir 800 mg every 8 hours for 9 days plus a single dose of raltegravir 400 mg on day 10 followed by a washout period and a single dose of raltegravir 400 mg on day 38, or the same medication in reverse order. Blood samples for pharmacokinetics were collected and pharmacokinetic parameters were calculated. RESULTS: The geometric mean (GM) of raltegravir area under the concentration-time curve (AUC)(0-12h) and maximum plasma concentration (C(max)) for raltegravir + boceprevir vs raltegravir alone were 4.27 (95% confidence interval [CI], 3.22-5.66) vs 4.04 (95% CI, 3.09-5.28) mg * hour/L and 1.06 (95% CI, .76-1.49) vs 0.93 (95% CI, .70-1.23) mg/L, respectively. GM ratio estimates of raltegravir AUC(0-12h) and C(max) for raltegravir + boceprevir vs raltegravir alone were 1.04 (90% CI, .88-1.22) and 1.11 (90% CI, .91-1.36), respectively. The GM of boceprevir AUC(0-8h), C(max), and C(8h) were 5.45 (95% CI, 5.11-5.81) mg * hour/L, 1.88 (95% CI, 1.72-2.06) mg/L, and 0.09 (95% CI, .07-.11) mg/L, respectively. These data are comparable to those from historical controls. CONCLUSIONS: Due to the absence of a clinically significant drug interaction, raltegravir can be recommended for combined HIV/HCV treatment including boceprevir. CLINICAL TRIALS REGISTRATION: NCT01288417.

Lack of a clinically significant drug-drug interaction in healthy volunteers between the HCV protease inhibitor boceprevir and the proton pump inhibitor omeprazole.

OBJECTIVES: Proton pump inhibitors (PPIs) can limit the solubility of concomitant drugs, which can lead to decreased absorption and exposure. Reduced efficacy can be a consequence and in the case of an antimicrobial agent this may contribute to development of resistance. Patients chronically infected with the hepatitis C virus can be treated with a boceprevir-containing regimen and it is relevant to know if interactions between PPIs and boceprevir exist. This study was designed to investigate the influence of a frequently used PPI, omeprazole, on the pharmacokinetics of boceprevir and vice versa. METHODS: In this open-label, three-period, randomized, cross-over, Phase I study, healthy subjects were randomly assigned to 40 mg of omeprazole once daily for 5 days, 800 mg of boceprevir three times daily for 5 days and 40 mg of omeprazole once daily + 800 mg of boceprevir three times daily for 5 days, or the same treatment in a different order. Every treatment was followed by a wash-out period. At day 5 of every treatment pharmacokinetic blood sampling was performed for 8 h after medication intake. ClinicalTrials.gov: NCT01470690. RESULTS: All 24 subjects (15 males) completed the study and no serious adverse events were reported. Geometric mean ratios (90% CI) of the area under the plasma concentration-time curve up to 8 h (AUC0-8) and maximum plasma concentration (Cmax) of boceprevir with omeprazole versus boceprevir alone were 0.92 (0.87-0.97) and 0.94 (0.86-1.02), respectively. For omeprazole these values were 1.06 (0.90-1.25) for AUC0-8 and 1.03 (0.85-1.26) for Cmax for the combination versus omeprazole alone. CONCLUSIONS: Omeprazole did not have a clinically significant effect on boceprevir exposure, and boceprevir did not affect omeprazole exposure.

A population pharmacokinetics analysis assessing the exposure of raltegravir once-daily 1200 mg in pregnant women living with HIV.

Once-daily two 600 mg tablets (1200 mg q.d.) raltegravir offers an easier treatment option compared to the twice-daily regimen of one 400 mg tablet. No pharmacokinetic, efficacy, or safety data of the 1200 mg q.d. regimen have been reported in pregnant women to date as it is challenging to collect these clinical data. This study aimed to develop a population pharmacokinetic (PopPK) model to predict the pharmacokinetic profile of raltegravir 1200 mg q.d. in pregnant women and to discuss the expected pharmacodynamic properties of raltegravir 1200 mg q.d. during pregnancy based on previously reported concentration-effect relationships. Data from 11 pharmacokinetic studies were pooled (n = 221). A two-compartment model with first-order elimination and absorption through three sequential transit compartments best described the data. We assessed that the bio-availability of the 600 mg tablets was 21% higher as the 400 mg tablets, and the bio-availability in pregnant women was 49% lower. Monte-Carlo simulations were performed to predict the pharmacokinetic profile of 1200 mg q.d. in pregnant and nonpregnant women. The primary criteria for efficacy were that the lower bound of the 90% confidence interval (CI) of the concentration before next dose administration (Ctrough ) geometric mean ratio (GMR) of simulated pregnant/nonpregnant women had to be greater than 0.75. The simulated raltegravir Ctrough GMR (90% CI) was 0.51 (0.41-0.63), hence not meeting the primary target for efficacy. Clinical data from two pregnant women using 1200 mg q.d. raltegravir showed a similar Ctrough ratio pregnant/nonpregnant. Our pharmacokinetic results support the current recommendation of not using the raltegravir 1200 mg q.d. regimen during pregnancy until more data on the exposure-response relationship becomes available.

Effect of Pregnancy and Concomitant Antiretrovirals on the Pharmacokinetics of Tenofovir in Women With HIV Receiving Tenofovir Disoproxil Fumarate-Based Antiretroviral Therapy Versus Women With HBV Receiving Tenofovir Disoproxil Fumarate Monotherapy.

Tenofovir disoproxil fumarate (TDF) is recommended as part of antiretroviral therapy (ART) for pregnant women with HIV and as monotherapy for pregnant women with hepatitis B virus (HBV) monoinfection at high risk of transmitting infection to their infants. Tenofovir (TFV) plasma exposures are reduced during pregnancy; however, concomitant antiretrovirals and the viral infection itself can also influence TFV pharmacokinetics. Our aim was to compare TFV pharmacokinetics in pregnant women receiving TDF-based ART, with or without a ritonavir-boosted protease inhibitor (r/PI), to pregnant women with HBV receiving TDF monotherapy. Non-r/PI regimens were primarily integrase strand transfer inhibitors or nonnucleoside reverse transcriptase inhibitor-based regimens. Data were combined from a pharmacokinetic study of pregnant women with HIV on ART (PANNA), and a study assessing TFV pharmacokinetics in pregnant women with HBV (iTAP). A total of 196 pregnant women, 59 with HIV (32 receiving r/PIs) and 137 with HBV monoinfection were included. Intraindividual TFV area under the plasma concentration-time curve from time 0 to 24 hours was 25%, 26%, and 21% lower during the third trimester compared to 1 month postpartum in women with HIV using TDF and an r/PI or TDF and non-r/PI and women with HBV receiving TDF monotherapy, respectively. TFV area under the plasma concentration-time curve from time 0 to 24 hours was similar in pregnant women receiving non-r/PI to pregnant women with HBV receiving TDF monotherapy (1.84 vs 1.86 µg • h/mL); however, pregnant women receiving TDF with an r/PI had higher exposures (2.41 µg • h/mL; P < .01). Pregnancy reduces TFV exposure and the relative size was not impacted by concomitant antiretroviral drugs or viral infection, but a drug-drug interaction between TDF and r/PI remains during pregnancy, leading to higher exposures than those on TDF and non-r/PI or TDF monotherapy.

Assessment of Maternal and Fetal Dolutegravir Exposure by Integrating Ex Vivo Placental Perfusion Data and Physiologically-Based Pharmacokinetic Modeling.

Antiretroviral therapy during pregnancy reduces the risk of vertical HIV-1 transmission. However, drug dosing is challenging as pharmacokinetics (PK) may be altered during pregnancy. We combined a pregnancy physiologically-based pharmacokinetic (PBPK) modeling approach with data on placental drug transfer to simulate maternal and fetal exposure to dolutegravir (DTG). First, a PBPK model for DTG exposure in healthy volunteers was established based on physiological and DTG PK data. Next, the model was extended with a fetoplacental unit using transplacental kinetics obtained by performing ex vivo dual-side human cotyledon perfusion experiments. Simulations of fetal exposure after maternal dosing in the third trimester were in accordance with clinically observed DTG cord blood data. Furthermore, the predicted fetal trough plasma concentration (Ctrough ) following 50 mg q.d. dosing remained above the concentration that results in 90% of viral inhibition. Our integrated approach enables simulation of maternal and fetal DTG exposure, illustrating this to be a promising way to assess DTG PK during pregnancy.

Prediction of Fetal Darunavir Exposure by Integrating Human Ex-Vivo Placental Transfer and Physiologically Based Pharmacokinetic Modeling.

BACKGROUND: Fetal antiretroviral exposure is usually derived from the cord-to-maternal concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure-effect relationship. OBJECTIVE: The aim of this study was to incorporate placental transfer into a pregnancy physiologically based pharmacokinetic model to simulate and evaluate fetal darunavir exposure at term. METHODS: An existing and validated pregnancy physiologically based pharmacokinetic model of maternal darunavir/ritonavir exposure was extended with a feto-placental unit. To parameterize the model, we determined maternal-to-fetal and fetal-to-maternal darunavir/ritonavir placental clearance with an ex-vivo human cotyledon perfusion model. Simulated maternal and fetal pharmacokinetic profiles were compared with observed clinical data to qualify the model for simulation. Next, population fetal pharmacokinetic profiles were simulated for different maternal darunavir/ritonavir dosing regimens. RESULTS: An average (±standard deviation) maternal-to-fetal cotyledon clearance of 0.91 ± 0.11 mL/min and fetal-to-maternal clearance of 1.6 ± 0.3 mL/min was determined (n = 6 perfusions). Scaled placental transfer was integrated into the pregnancy physiologically based pharmacokinetic model. For darunavir 600/100 mg twice a day, the predicted fetal maximum plasma concentration, trough concentration, time to maximum plasma concentration, and half-life were 1.1, 0.57 mg/L, 3, and 21 h, respectively. This indicates that the fetal population trough concentration is higher or around the half-maximal effective darunavir concentration for a resistant virus (0.55 mg/L). CONCLUSIONS: The results indicate that the population fetal exposure after oral maternal darunavir dosing is therapeutic and this may provide benefits to the prevention of mother-to-child transmission of human immunodeficiency virus. Moreover, this integrated approach provides a tool to prevent fetal toxicity or enhance the development of more selectively targeted fetal drug treatments.

Pharmacokinetics, Short-term Safety and Efficacy of the Approved Once-daily Darunavir/Ritonavir Dosing Regimen in HIV-infected Children.

In this multicenter pharmacokinetic study in HIV-infected children (6-12 years of age), we validated the approved once-daily darunavir/ritonavir dosing recommendations. The geometric mean darunavir area under the plasma concentration-time curve was 63.1 h·mg/L, substantially lower than the mean value observed in adults. However, all trough levels were adequate, and short-term virologic outcome was good. These data support the use of the darunavir/ritonavir once-daily dosing recommendations.

The ARRIBA concept: adequate resorption of ribavirin.

BACKGROUND: Adequate ribavirin exposure is essential for optimal sustained virological response (SVR) rates in chronic HCV treatment. It has been proposed that the area under the concentration-time curve up to 4 h after intake of ribavirin (AUC0-4 h) of the first weight-based ribavirin dose should be ≥1.755 mg•h/l to guarantee the highest chance of SVR. Our ARRIBA concept comprises a test dose of ribavirin to select the optimal starting dose to achieve adequate exposure. This study aims to evaluate whether adequate exposure can be achieved after dose advice based on the AUC0-4 h of a single weight-based ribavirin test dose. METHODS: (Formerly) HCV-infected subjects received a single weight-based ribavirin test dose (<75 kg: 400 mg; ≥75 kg: 600 mg) and the AUC0-4 h was calculated. If ribavirin AUC0-4 h was ≥1.755 mg•h/l, subjects received the same dose 4 weeks later; if the AUC0-4 h was <1.755 mg•h/l, an adjusted dose was administered. The ribavirin AUC0-4 h was recorded again. The primary outcome was the proportion of subjects with an AUC0-4 h ≥1.755 mg•h/l after the second dose. RESULTS: A total of 26 subjects were included. The geometric mean (95% CI) ribavirin AUC0-4 h was 1.67 (1.44-1.92) mg•h/l with 9 subjects (35%) reaching the target AUC on day 1. Thus, on day 29, 17 subjects (65%) received an adjusted dose. The geometric mean (95% CI) AUC0-4 h increased to 1.90 (1.62-2.21) mg•h/l and then 16 subjects (62%) had an AUC0-4 h ≥1.755 mg•h/l, which is significantly higher than day 1 (P<0.05). CONCLUSIONS: Our ARRIBA concept of a ribavirin test dose, with dose adjustment if necessary, leads to an increased proportion of patients with an AUC≥1.755 mg•h/l compared to traditional weight-based ribavirin dosing.

Effect of fosamprenavir/ritonavir on the pharmacokinetics of single-dose olanzapine in healthy volunteers.

Psychosis and other mental illnesses are common in HIV-infected patients. Olanzapine is one of the preferred antipsychotic agents for the treatment of schizophrenia. Olanzapine is primarily metabolised by CYP1A2 and uridine diphosphate glucuronosyltransferase (UGT). High-dose ritonavir has been shown to increase olanzapine elimination through induction of CYP1A2 and/or UGT, but the effect of low-dose ritonavir on olanzapine pharmacokinetics is unknown. Fosamprenavir is an HIV protease inhibitor that is boosted by low-dose ritonavir. To compensate for the induction of olanzapine metabolism by fosamprenavir/ritonavir, we hypothesised that a dose increase of olanzapine to 15 mg with fosamprenavir/ritonavir would lead to a similar area under the concentration-time curve (AUC) compared with olanzapine 10 mg alone. An open-label, randomised, two-period, cross-over, single-centre trial was conducted in 24 healthy volunteers. Subjects were randomised to one of the following treatments: (A) fosamprenavir/ritonavir 700/100 mg twice daily (b.i.d.) for 16 days with a single dose of olanzapine 15 mg on Day 13, a wash-out period of 31 days and a single dose of olanzapine 10 mg on Day 48; or (B) the same medication in reverse order. Twenty subjects completed the trial. The geometric mean ratios (90% CI) of olanzapine AUClast, maximum drug concentration (C(max)) and apparent elimination half-life (t(1/2)) when taken with fosamprenavir/ritonavir versus olanzapine alone were 1.00 (0.93-1.08), 1.32 (1.18-1.47) and 0.68 (0.63-0.74), respectively. Fosamprenavir/ritonavir 700/100 mg b.i.d. appeared to induce olanzapine metabolism. We therefore propose a 50% dosage increase of olanzapine when combining with a ritonavir-boosted protease inhibitor.

Pharmacokinetics of pediatric lopinavir/ritonavir tablets in children when administered twice daily according to FDA weight bands.

BACKGROUND: Lopinavir/ritonavir (LPV/r) pediatric tablets (100/25 mg) are approved by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) as part of combination antiretroviral therapy. Dosing is based on body weight bands or body surface area under FDA approval and only body surface area by the EMA. This can lead to a different recommended dose. In addition, weight band-based dosing has not been formally studied in the target population. We evaluated the pharmacokinetics (PK) of LPV/r in children, administered twice daily according to the FDA weight bands, using pediatric tablets. METHODS: Fifty-three HIV-infected children were included in the PK substudy of the Paediatric European Network for the Treatment of AIDS 18 trial (KONCERT). In this study, children were randomized to receive LPV/r twice or once daily, according to FDA weight bands. A PK assessment was performed in 17, 16 and 20 children in the 15-25 kg, ≥ 25-35 kg and >35 kg weight band, respectively, while children took the tablets twice daily. Rich sampling was performed, and PK parameters were calculated by noncompartmental analysis. Given the high percentage of Asian children, it was also tested whether there was a difference in PK parameters between Asian and non-Asian children. RESULTS: For the total group, LPV geometric mean AUC0-12, Cmax and C12 were 106.9 h × mg/L, 12.0 mg/L and 4.9 mg/L, respectively. There were no significant differences in LPV PK parameters between the weight bands. In addition, weight was not found to be associated with variability in Cmax, C12 or AUC0-12 for the LPV PK parameters. CONCLUSIONS: FDA weight band-based dosing recommendations provide adequate exposure to LPV when using LPV/r pediatric tablets.

The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1-infected pregnant women.

OBJECTIVE: To describe the pharmacokinetics of tenofovir and emtricitabine in the third trimester of pregnant HIV-infected women and at postpartum. DESIGN: A nonrandomized, open-label, multicentre phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. METHODS: HIV-infected pregnant women treated with the nucleotide/nucleoside analogue reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF 300 mg; equivalent to 245 mg tenofovir disoproxil) and/or emtricitabine (FTC 200 mg) were included in the study. Twenty-four-hour pharmacokinetic curves were recorded in the third trimester (preferably week 33) and postpartum (preferably week 4-6). Collection of a cord blood sample and maternal sample at delivery was optional. Pharmacokinetic parameters were calculated using WinNonlin software version 5.3. Statistical analysis was conducted using SPSS version 16.0. RESULTS: Thirty-four women were included in the analysis. Geometric mean ratios of third trimester vs. postpartum [90% confidence interval (CI)] were 0.77 (0.71-0.83) for TDF area under the curve (AUC0-24 h); 0.81 (0.68-0.96) for TDF Cmax and 0.79 (0.70-0.90) for TDF C24 h and 0.75 (0.68-0.82) for FTC AUC0-24 h; and 0.87 (0.77-0.99) for FTC Cmax and 0.77 (0.52-1.12) for FTC C24 h. The viral load close to delivery was less than 200  copies/ml in all but one patient, the average gestational age at delivery was 38 weeks. All children were tested HIV-negative and no congenital abnormalities were reported. CONCLUSION: Although pharmacokinetic exposure of the NRTIs TDF and FTC during pregnancy is approximately 25% lower, this was not associated with virological failure in this study and did not result in mother-to-child transmission.