Search

This study aimed to characterize adverse drug reactions (ADRs) to hydroxychloroquine in the setting of COVID‐19, occurring in Italy in the period March to May 2020. The analysis of the combination therapy with azithromycin or/and lopinavir/ritonavir as well as a comparison with ADRs reported throughout 2019 was performed. ADRs collected by the Italian National Network of Pharmacovigilance were analyzed for their incidence, seriousness, outcome, coadministered drugs, and Medical Dictionary for Regulatory Activities classification. A total of 306 reports were gathered for the quarter of 2020: 54% nonserious and 46% serious, and half of the latter required either the hospitalization or its prolongation. However, most of them were either completely recovered (26%) or in the process of recovery (45%), except for 9 fatal cases. Throughout 2019, 38 reports were collected, 53% nonserious and 47% serious, but no deaths had been reported. Diarrhea, prolonged QT interval, and hypertransaminasemia were the most frequently ADRs reported in 2020, significantly higher than 2019 and specific for COVID‐19 subjects treated with hydroxychloroquine. The logistic regression analyses demonstrated that the likelihood of serious ADRs, QT prolongation, and diarrhea significantly increased with hydroxychloroquine dosage. Coadministration of lopinavir/ritonavir and hydroxychloroquine showed a positive correlation with diarrhea and hypertransaminasemia and a negative relationship with the ADR seriousness. The combination therapy with azithromycin was another independent predictor of a serious ADR. Off‐label use of hydroxychloroquine for COVID‐19, alone or in combination regimens, was associated with increased incidence and/or seriousness of specific ADRs in patients with additional risk factors caused by the infection. [ABSTRACT FROM AUTHOR]

Although people living with human immunodeficiency virus and other comorbidities are expected to experience more grievous consequences with corona virus disease 2019 (COVID‐19), recent cohort studies did not indicate this. Antiretrovirals (ARVs) might have a prophylactic role in these patients. The purpose of this study was to review the most recently published articles on the possible role of ARVs for pre‐ or postexposure prophylaxis against COVID‐19. From June to October 2020, we searched scientific databases using specific key words to identify ongoing trials or articles published before October 2020 investigating any subgroups of ARVs for prophylaxis against COVID‐19. Apart from molecular docking studies, in vitro, animal, and human studies are very limited for evaluating the prophylactic role of ARVs against severe acute respiratory syndrome‐corona virus 2 (SARS‐CoV‐2) infection. According to our findings, there is no definite evidence to support use of protease inhibitors for this purpose, despite the promising results of molecular studies and limited clinical evidence for ritonavir‐boosted lopinavir, darunavir, and nelfinavir when used early in the course of the disease. Nucleotide/nucleoside reverse‐transcriptase inhibitors (NRTI) also have shown binding affinity to main enzymes of SARS‐CoV‐2 in molecular, in vitro, and animal studies. NRTIs like tenofovir and emtricitabine might exhibit a prophylactic role against SARS‐CoV‐2 infection. In conclusion, currently there is no evidence to justify the use of ARVs for prophylaxis against COVID‐19. [ABSTRACT FROM AUTHOR]

Bupivacaine, a local anesthetic, is commercialized as a racemic mixture of R-bupivacaine and S-bupivacaine enantiomers. HIV infection increases the expression of placental P-glycoprotein (P-gp), and antiretroviral (ARV) therapy inhibits cytochrome P450 3A and P-gp. The present study evaluates the kinetic disposition of bupivacaine enantiomers in HIV-infected parturient women on ARV therapy. In this study, HIV-infected parturient women (n = 10) treated with zidovudine, lamivudine, lopinavir, and ritonavir were investigated. Anesthesia and/or analgesia was achieved by the administration of 0.5% racemic bupivacaine hydrochloride with 1:200000 epinephrine in the epidural space at doses of 2.5 to 22.5 mg. Maternal serial blood samples were obtained at the time immediately before and 5, 15, 30, 45, and 60 minutes and 2, 4, 6, 8, 10, 12, and 14 hours after administration of the bupivacaine. At the time of delivery, samples of maternal and umbilical cord vein blood were also collected. The results suggest that bupivacaine pharmacokinetics are enantioselective, revealing higher maternal plasma concentrations of the R-bupivacaine enantiomer (area under the total plasma concentration-time curve was calculated by the trapezoid method with extrapolation to infinity/dose(S)/(R) = 0.91; P < .05). The plasma unbound fraction of the drug (0.09 vs 0.06) and the umbilical cord vein/maternal plasma ratio (0.47 vs 0.39) were higher for the R-bupivacaine enantiomer than the S-bupivacaine enantiomer (P < .05). ARV therapy with ritonavir confers an enantioselective interaction between the enantiomers of bupivacaine and placental P-gp, producing greater inhibition of efflux transport of the R-bupivacaine enantiomer. Possible changes in the well-being of the fetuses of mothers under analgesia may be a consequence of the increased placental transfer of bupivacaine enantiomers to the fetal circulation. [ABSTRACT FROM AUTHOR]

Although current quetiapine labeling recommends that its dosage should be lowered 6‐fold when coadministered with strong cytochrome P450 (CYP)3A inhibitors, a reported case of coma in a patient receiving quetiapine with lopinavir and ritonavir prompted the reevaluation of labeling recommendations for the dosing of quetiapine when coadministered with human immunodeficiency virus (HIV) protease inhibitors. Literature and database (FDA Adverse Event Reporting System and United States Symphony Health Solutions' Integrated Dataverse Database) searches allowed us to identify cases of coma and related adverse events involving the coadministration of quetiapine and HIV protease inhibitors and to estimate the frequency of concomitant use. Literature review and physiologically based pharmacokinetic modeling allowed us to estimate the potential for CYP3A inhibition to contribute to adverse events related to HIV protease inhibitor–quetiapine coadministration. We identified excess sedation following coadministration of quetiapine and an HIV protease inhibitor in 3 reports without obvious confounders. In prescription claims data, 0.4% of quetiapine patients were dispensed a concurrent ritonavir prescription. The quetiapine dose was not reduced on ritonavir initiation in 90% of therapy episodes. Available data indicate to us that all HIV protease inhibitors combined with ritonavir are likely to be strong CYP3A inhibitors. We predicted that ritonavir would increase quetiapine exposure comparable to the strong CYP3A inhibitor ketoconazole. The current dosing recommendations for use of quetiapine with strong CYP3A inhibitors (ie, 6‐fold lower quetiapine dose) are appropriate and should be followed when quetiapine is coadministered with HIV protease inhibitors. [ABSTRACT FROM AUTHOR]

Lopinavir/ritonavir (LPV/r) is recommended by the World Health Organization as first‐line treatment for HIV‐infected infants and young children. We performed a composite population pharmacokinetic (PK) analysis on LPV plasma concentration data from 6 pediatric and adult studies to determine maturation and formulation effects from infancy to adulthood. Intensive PK data were available for infants, children, adolescents, and adults (297 intensive profiles/1662 LPV concentrations). LPV PK data included 1 adult, 1 combined pediatric‐adult, and 4 pediatric studies (age 6 weeks to 63 years) with 3 formulations (gel‐capsule, liquid, melt‐extrusion tablets). LPV concentrations were modeled using nonlinear mixed effects modeling (NONMEM v. 7.3; GloboMax, Hanover, Maryland) with a one compartment semiphysiologic model. LPV clearance was described by hepatic plasma flow (QHP) times hepatic extraction (EH), with EH estimated from the PK data. Volume was scaled by linear weight (WT/70)1.0. Bioavailability was assessed separately as a function of hepatic extraction and the fraction absorbed from the gastrointestinal tract. The absorption component of bioavailability increased with age and tablet formulation. Monte Carlo simulations of the final model using current World Health Organization weight‐band dosing recommendations demonstrated that participants younger than 6 months of age had a lower area under the drug concentration–time curve (94.8 vs >107.4 μg hr/mL) and minimum observed concentration of drug in blood plasma (5.0 vs > 7.1 μg/mL) values compared to older children and adults. Although World Health Organization dosing recommendations include a larger dosage (mg/m2) in infants to account for higher apparent clearance, they still result in low LPV concentrations in many infants younger than 6 months of age receiving the liquid formulation. [ABSTRACT FROM AUTHOR]

Management of comorbidities and medications is complex in HIV-1-infected patients. The overall objective of this project was to develop separate physiologically based pharmacokinetic (PBPK) substrate models for the protease inhibitors darunavir and lopinavir. These protease inhibitors are used in the treatment of HIV infection. Both darunavir and lopinavir are coadministered with another medication that inhibits cytochrome (CYP) 3A. The current project focused on PBPK modeling for darunavir and lopinavir coadministered with ritonavir. Darunavir and lopinavir PBPK models that accounted for ritonavir CYP3A inhibition effects (linked PBPK models) were developed. The linked PBPK models were then used to predict the effect on darunavir or lopinavir exposure from CYP modulators. In the next step, the predicted effect of hepatic impairment was evaluated. Additional exploratory analyses predicted CYP3A inhibition effects on darunavir or lopinavir exposure in simulated hepatically impaired subjects. The linked PBPK models reasonably predicted darunavir or lopinavir exposure based on simulations with CYP inhibitors or inducers. Exploratory simulations using the linked darunavir or lopinavir PBPK models indicated CYP3A inhibition may further increase darunavir or lopinavir exposure in patients with hepatic impairment. [ABSTRACT FROM AUTHOR]

Elvitegravir (EVG) is an HIV strand transfer integrase inhibitor approved for the treatment of HIV infection as a part of antiretroviral regimens containing cobicistat (COBI) or ritonavir (RTV) as a booster. The population pharmacokinetics of EVG in treatment-naive and -experienced HIV patients was determined, and the effects of demographic, biometric, and formulation covariates on EVG pharmacokinetics (PK) were evaluated. Data from 31 clinical studies (25 in healthy subjects, 6 phase 1b to phase 3 in HIV-1-infected patients) with COBI-boosted EVG studies (as EVG/co or EVG/COBI/FTC/TDF single-tablet regimen) or RTV-boosted EVG studies (EVG/r) were analyzed using NONMEM. The effect of the covariates age, sex, race, health status (healthy volunteers vs HIV patients), weight, body mass index (BMI), body surface area (BSA), creatinine clearance (estimated GFR), and formulation were evaluated. EVG PK, with COBI or RTV, was described by a 2-compartment model, with first-order absorption and elimination and an absorption lag time. A statistically significant, but not clinically relevant, effect of BSA on EVG clearance (CL) was observed. Coadministration of atazanavir or lopinavir with EVG/r had an effect on EVG CL consistent with the known interaction with these agents. No other covariate had a meaningful effect on EVG PK. EVG PK was well described in a population PK model with HIV-infected patients, with low PK variability and no relevant effect of demographic or biometric covariates. [ABSTRACT FROM AUTHOR]

Pregnancy and food insecurity may impact antiretroviral (ART) pharmacokinetics (PK), adherence and response. We sought to quantify and characterize the PK of lopinavir/ritonavir (LPV/r) and efavirenz (EFV) by pregnancy and nutritional status among HIV-infected women in Tororo, Uganda. In 2011, 62/225 ante-partum/post-partum single dried blood spot samples DBS and 43 post-partum hair samples for LPV/r were derived from 116 women, 51/194 ante-/post-partum DBS and 53 post-partum hair samples for EFV from 105 women. Eighty percent of Ugandan participants were severely food insecure, 26% lost weight ante-partum, and median BMI post-partum was only 20.2 kg/m2. Rich PK-data of normally nourished (pregnant) women and healthy Ugandans established prior information. Overall, drug exposure was reduced (LPV −33%, EFV −15%, ritonavir −17%) compared to well-nourished controls ( P < 0.001), attributable to decreased bioavailability. Pregnancy increased LPV/r clearance 68% ( P < 0.001), whereas EFV clearance remained unchanged. Hair concentrations correlated with plasma-exposure ( P < 0.001), explaining 29% PK-variability. In conclusion, pregnancy and food insecurity were associated with lower ART exposures in this cohort of predominantly underweight women, compared to well-nourished women. Much variability in plasma-exposure was quantified using hair concentrations. Addressing malnutrition as well as ART-PK in this setting should be a priority. [ABSTRACT FROM AUTHOR]

Background A previous study investigating coadministration of etravirine, a nonnucleoside reverse transcriptase inhibitor, and lopinavir/ritonavir soft-gel formulation resulted in nonclinically relevant changes in etravirine and lopinavir exposure. The current study evaluated the pharmacokinetic interaction between etravirine and the lopinavir/ritonavir melt extrusion formulation. Method Sixteen human immunodeficiency virus (HIV)-negative volunteers were randomized to either treatment sequence A/B or B/A, with 14 days- washout between treatments (treatment A: etravirine 200 mg bid for 8 days; treatment B: lopinavir/ritonavir 400/100 mg bid for 16 days with etravirine 200 mg bid on days 9-16). Steady-state pharmacokinetics were assessed for all antiretrovirals alone and coadministered; pharmacokinetic parameters were obtained by noncompartmental analysis. Safety and tolerability were assessed. Results Coadministration of etravirine and lopinavir/ritonavir resulted in a 35% decrease in etravirine exposure. Smaller decreases (<13%) were observed in lopinavir and ritonavir exposure. Six volunteers reported headache; 1 grade 3 triglyceride increase was reported. Conclusion Lopinavir/ritonavir induced etravirine metabolism to a similar extent as most other boosted HIV protease inhibitors. The short-term coadministration of etravirine and lopinavir/ritonavir was well tolerated and did not lead to increased incidences of adverse events. [ABSTRACT FROM AUTHOR]

A study was conducted in healthy adults (n = 19) to evaluate the pharmacokinetics of lopinavir/ritonavir when coadministered with efavirenz. Participants were administered lopinavir/ritonavir 400/100 mg alone twice daily (bid) from the morning of day 1 through the morning of day 10, and then lopinavir/ritonavir 500/125 mg bid was coadministered with efavirenz 600 mg every evening (qhs) from the evening of day 10 through day 20. Lopinavir and ritonavir exposures when administered alone versus with efavirenz were determined on days 10 and 20 and compared using point estimates and 90% confidence intervals. The point estimates for the ratios of lopinavir maximum observed plasma concentration (Cmax), plasma concentration prior to morning dosing (Ctrough), and area under the plasma concentration-time curve over a dosing interval (AUC12) were 1.121, 0.954, and 1.060, respectively. The lopinavir/ritonavir dose of 500/125 mg bid administered with efavirenz most closely approximates the pharmacokinetic exposure of lopinavir/ritonavir 400/100 mg bid administered alone. [ABSTRACT FROM PUBLISHER]

The authors compared the pharmacokinetics of lopinavir (LPV) and ritonavir (RTV) between women and men. This 2-step, multicenter, pharmacokinetic study enrolled human immunodeficiency virus (HIV)–infected adults on lopinavir/ritonavir (LPV/r) capsules (400/100 mg bid) plus 1 or more nucleoside reverse transcriptase inhibitors. All participants underwent 12-hour pharmacokinetic sampling. The pharmacokinetic sampling was repeated in participants receiving the LPV/r tablet formulation. Step 1 enrolled 37 women and 40 men; step 2 included 42 participants from step 1 plus 35 new participants (39 women and 38 men). LPV pharmacokinetics in women and men were not significantly different with either formulation. Women had significantly higher median RTV AUC0-12 h with both the soft-gel capsule (SGC) and tablet formulations (SGC: 5395 vs 4119 ng·h/mL, P = .026; tablet: 5310 vs 3941 ng·h/mL, P = .012), higher median Cmax (SGC: 802 vs 635 ng/mL, P = .032; tablet: 773 vs 570 ng/mL, P = .006), and lower median CL/F (SGC: 18.54 vs 24.31 L/h, P = .026; tablet: 18.83 vs 25.37 L/h, P = .012). RTV CL/F was slower in women after weight adjustment with both formulations. The pharmacokinetics of LPV in the SGC and tablet formulations are comparable in HIV-infected patients. Women had higher RTV AUC0-12 h and lower CL/F with both formulations. The mechanism of the sex difference in RTV CL/F warrants elucidation. [ABSTRACT FROM PUBLISHER]

Background: Immune mediated changes in circulating α-1-acid glycoprotein (AAG), a type 1 acute phase protein, which binds protease inhibitors (PI), may alter protein binding and contribute to PI’s pharmacokinetic (PK) variability. Methods: In a prospective, 2-phase intensive PK study on antiretroviral naive human immunodeficiency virus (HIV)-infected subjects treated with a lopinavir-/ritonavir-based regimen, steady state PK sampling and AAG assays were performed at weeks 2 and 16 of treatment. Results: Median entry age was 43 years (n = 16). Median plasma log10 HIV-1 RNA, CD4 T-cell counts, and AAG were 5.16 copies/mL, 28 cells/µL, and 143 mg/dL, respectively.The total lopinavir area under the concentration time curve (AUC12_total) and maximum concentration (Cmax_total) changed linearly with AAG at mean rates of 16±7 mg*hr/L (slope ± SE); P = .04, and 1.6 ± 0.6 mg/L, P = .02, per 100 mg/dL increase in AAG levels, respectively (n = 15).A 29% drop in AAG levels between week 2 and week 16 was associated with 14% (geometric mean ratio [GMR] = 0.86; 90% confidence interval [CI] = 0.74-0.98) and 13% (GMR = 0.87; 90% CI = 0.79-0.95) reduction in AUC12_total and Cmax_total, respectively. Neither free lopinavir PK parameters nor antiviral activity (HIV-1 RNA average AUC minus baseline) was affected by change in plasma AAG. Conclusions: Changes in plasma AAG levels alter total lopinavir concentrations, but not the free lopinavir exposure or antiviral activity. This observation may have implications in therapeutic drug monitoring. [ABSTRACT FROM PUBLISHER]

Raltegravir is an HIV-1 integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. Data from healthy volunteers demonstrate that raltegravir is rapidly absorbed with a mean half-life of approximately 7 to 12 hours, with steady state achieved in approximately 2 days. Raltegravir is characterized by both high intra- and interindividual variabilities, although neither gender, race, age, body mass index, food intake, nor renal or hepatic insufficiency has a clinically meaningful effect on raltegravir pharmacokinetics. Raltegravir lacks activity as a perpetrator of drug–drug interactions and demonstrates a low propensity to be subject to drug–drug interactions. Raltegravir is metabolized primarily by UGT1A1 and is not affected by P450 inhibitors or inducers. Inhibitors of UGT1A1 (eg, atazanavir) can increase plasma concentrations of raltegravir, although this increase has not been found to be clinically meaningful. Likewise, inducers of UGT1A1 (eg, rifampin) can reduce plasma concentrations of raltegravir, and the clinical significance of this reduction is being investigated in ongoing clinical studies. Raltegravir demonstrates favorable clinical pharmacology and a drug interaction profile that permits administration to a wide, demographically diverse patient population and coadministration with many other therapeutic agents, including antiretroviral agents and supportive medications, without restrictions or dose adjustment. [ABSTRACT FROM PUBLISHER]

The objective of this investigation was to evaluate the pharmacokinetic interaction of lopinavir/ritonavir (LPV/r) with BILR 355. In group A, 26 healthy participants were administered LPV/r (400mg/100mg) twice daily for 14 days, followed by coadministration of BILR 355, 150 mg twice daily for an additional 7 days. Pharmacokinetic assessments were performed on days 14 and 21. In group B, 8 healthy participants were given BILR 355/ritonavir (BILR 355/r, 150mg/100mg) twice daily for 7 days. The pharmacokinetic data from group B (BILR 355/r–alone group) were also pooled with group B subjects from 3 similar phase I drug–drug interaction trials performed in parallel to this study. Coadministration with LPV/r resulted in a 51% decrease in steady-state area under plasma concentration-time curve from 0 to 12 hours (AUC0-12,ss) and steady-state maximum measured plasma concentration over a dosing interval (Cmax,ss) and a 50% decrease in steady-state plasma concentration 12 hours post last dosing (C12,ss) for BILR 355. Exposure to LPV was not changed after coadministration. BILR 355/r was well tolerated in this study. There was no evidence of increased risk of lopinavir or ritonavir toxicity upon coadministration with BILR 355. [ABSTRACT FROM PUBLISHER]

S/GSK1349572 is an unboosted, once-daily integrase inhibitor with a novel resistance profile. As standard of care for patients infected with HIV is combination therapy, the potential interaction between S/GSK1349572 and ritonavir-boosted protease inhibitors was evaluated. In an open-label, repeat-dose, 2-period, 2-sequence crossover study in healthy participants, S/GSK1349572 was administered at 30 mg once daily for 5 days, followed by randomization to lopinavir/ritonavir 400/100 mg twice daily or darunavir/ritonavir 600/100 mg twice daily coad-ministered with S/GSK1349572 30 mg once daily for 14 days. There was no washout between periods. Serial pharmacokinetic (PK) samples and safety assessments were obtained throughout the study. Thirty of 31 participants completed the study (15 participants per group). Treatment comparisons of steady-state S/GSK1349572 PK parameters demonstrated that coadministration of lopinavir/ritonavir had no significant effect on steady-state PK of S/GSK1349572. Coadministration of darunavir/ritonavir resulted in a nonclinically significant reduction in steady-state plasma S/GSK1349572 exposures. Plasma S/GSK1349572 AUC(0-τ ), Cmax, and Cτdecreased by 22%, 11%, and 38%, respectively, on average. S/GSK1349572 was well tolerated with no serious adverse events (AEs) or withdrawals due to drug-related AEs. The most frequent drug-related AEs were diarrhea, dizziness, and headache. No dosage adjustment for S/ GSK1349572 is required when used with lopinavir/ritonavir or darunavir/ritonavir. [ABSTRACT FROM PUBLISHER]

Guidelines recommend that when soft-gelatin capsules of lopinavir/ritonavir are co-administered with CYP3A4- inducing agents, doses should be increased to 4 capsules (533 mg/133 mg) twice daily. No evidence is available to guide dosing of lopinavir/ritonavir in tablet formulation in this setting. A single-center study is conducted to compare the pharmacokinetics of high-dose lopinavir/ritonavir in 34 patients on stable HAART regimens including 4 soft-gelatin capsules twice daily who then switch to 3 tablets (600 mg/150 mg) twice daily. Median C[submin] on soft-gelatin capsule and tablets is 4700 ng/mL (interquartile range [IQR] 2310, 6000 ng/mL) and 5640 ng/mL (IQR 4290, 8080 ng/mL), respectively, for those on inducing agents (n = 17). For patients not on inducing agents (n = 17), median C[submin] on soft-gelatin capsule and tablets is 5170 ng/mL (IQR 3640, 6210 ng/mL) and 5640 ng/mL (IQR 4290, 8080 ng/mL), respectively. Among treatment-experienced patients on lopinavir/ritonavir capsules 533/133 mg twice daily, a switch to tablets 600/150 mg twice daily produces comparable pharmacokinetics, regardless of whether they receive concomitant CYP3A4-inducing antiretroviral agents. [ABSTRACT FROM AUTHOR]