ritonavir and Vomiting

Twice-daily darunavir/ritonavir is indicated in treatment-experienced children (≥3 years). This study assessed once-daily administration in treatment-naïve adolescents.. Phase 2, 48-week, open-label, single-arm study evaluating pharmacokinetics, safety and efficacy of once-daily darunavir/ritonavir 800/100 mg in treatment-naïve, HIV-1-infected adolescents (≥12 to <18 years, ≥40 kg) with zidovudine/lamivudine or abacavir/lamivudine.. Twelve patients (67% female; median 14.4 years) were enrolled. After 24 and 48 weeks, respectively, 11 of 12 (92%) and 10 of 12 (83%) patients achieved viral load <50 copies/mL (intent-to-treat time-to-loss of virologic response); all had ≥1 log10 drop in viral load versus baseline. Median CD4 cell count increased by 175 and 221 cells/mm (intent-to-treat-noncompleter = failure) after 24 and 48 weeks, respectively. Eighty-three percent of patients were adherent to darunavir/ritonavir. One patient was never suppressed and 1 patient rebounded. No patients developed darunavir resistance-associated mutations or lost phenotypic susceptibility to any commercially available protease inhibitor or any background nucleoside reverse transcriptase inhibitor. Eleven patients (92%) reported ≥1 adverse event (AE), considered in 2 patients to be at least possibly related to darunavir (gastrointestinal-related events and dizziness). Four patients had ≥1 serious AE. Three patients reported ≥1 grade 3/4 AE; no serious or grade 3/4 AEs were considered darunavir related. No patients discontinued because of AEs.. Over 48 weeks, once-daily darunavir/ritonavir 800/100 mg plus NRTIs was effective and well-tolerated for treatment of HIV-1-infected, antiretroviral-naïve adolescents (≥12 to <18 years). These findings support use of once-daily darunavir/ritonavir 800/100 mg in this population.

Topics: Adolescent; Anemia; CD4 Lymphocyte Count; Darunavir; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Medication Adherence; Nausea; Neutropenia; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Time Factors; Viral Load; Vomiting; Zidovudine

To evaluate the efficacy, safety and tolerability of ritonavir-boosted tipranavir (TPV/r) in HIV-1-infected pediatric patients.. Open-label randomized pediatric trial (1182.14/PACTG1051) comparing TPV/r at two doses including an optimized background regimen.. HIV-1-infected patients (2-18 years) with plasma viral load 1500 copies/ml or more were randomized to TPV/r 290/115 or 375/150 mg/m twice-daily oral solution and optimized background regimen. Week 48 efficacy, safety and tolerability results were evaluated.. Children (n = 115; 97% treatment experienced) were randomized to low or high dose therapy. Eighty-eight remained on-treatment through 48 weeks. Baseline characteristics were similar between dose groups. At study entry, half of the HIV-1 isolates were resistant to all protease inhibitors. At 48 weeks, 39.7% low-dose and 45.6% high-dose TPV/r recipients had viral load less than 400 copies/ml and 34.5 and 35.1%, respectively, achieved viral load less than 50 copies/ml. Vomiting, cough and diarrhea were the most frequent adverse events. Grade 3 alanine aminotransferase elevations were observed in 6.3% of patients. No grade 4 alanine aminotransferase or grade 3/4 aspartate aminotransferase elevations were reported.. TPV/r achieved a sustained virologic response, showed a good safety profile and was well tolerated at either dose. In pediatric patients with high baseline resistance profiles, high-dose TPV/r tended to demonstrate a better sustained response.

Topics: Adolescent; Alanine Transaminase; Anti-HIV Agents; Biomarkers; Blood Coagulation Disorders; Child; Child, Preschool; Diarrhea; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Logistic Models; Male; Pyridines; Pyrones; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load; Vomiting

Previous research in healthy volunteers has demonstrated that rifampicin and adjusted doses of lopinavir/ritonavir soft-gel capsules resulted in adequate exposure to lopinavir. Our objective was to study the combined use of rifampicin and the newly introduced lopinavir/ritonavir tablets.. A total of 40 healthy volunteers were planned to start with 600 mg rifampicin once daily from days 1-5. From days 6-15, volunteers were randomized to receive lopinavir/ritonavir tablets dosed as either 600/150 or 800/200 mg twice daily, both in addition to 600 mg rifampicin once daily. A 12 h pharmacokinetic curve was planned on day 15. Safety assessments were conducted regularly throughout the study period.. Eleven volunteers started as the first group in this study. No major complaints occurred during day 1-5 (rifampicin only). After addition of lopinavir/ritonavir, eight volunteers suffered from both nausea and vomiting, one from nausea only, and one from vomiting only. On day 7, increases in aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels were reported in all volunteers and on day 8, the study was prematurely terminated. The AST/ALT levels continued to rise and peaked (grade 2, n = 2; grade 3, n = 1; grade 4, n = 8) on days 9-10. All values returned to normal within 6 weeks.. The study showed a high incidence of adverse events when a higher than standard dose of the new lopinavir/ritonavir tablets was combined with rifampicin. In the future, this drug combination should not be given to healthy volunteers. Liver function should be carefully monitored when rifampicin and lopinavir/ritonavir are combined in patients.

Topics: Adult; Alanine Transaminase; Antibiotics, Antitubercular; Aspartate Aminotransferases; Drug Administration Schedule; Drug Combinations; Drug Interactions; Female; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Nausea; Pyrimidinones; Rifampin; Ritonavir; Tablets; Vomiting

To investigate the influence of combined ritonavir (RTV) and saquinavir (soft-gelatin capsule formulation; SQV) on systemic exposure to SQV with a view to optimizing the dosing regimen of combined RTV and SQV antiretroviral therapy.. In this open labelled, randomized, parallel group study, SQV and RTV were administered twice daily for 14 days to groups of eight healthy subjects. The two antiretrovirals were either administered alone (800 mg SQV, regimen A, and 400 mg RTV, B) or in combination at various dose levels (RTV : SQV: 400 : 400 mg, C; 300 : 600 mg, D; 200 : 800 mg, E; 300 : 800 mg, F; 400 : 800 mg, G; and 400 : 600 mg, H). Pharmacokinetic parameters of saquinavir and ritonavir were determined and adverse events, vital signs, and clinical laboratory variables recorded.. RTV substantially increased the plasma concentration of saquinavir for all dose combinations, compared with SQV alone. Based on the primary statistical analysis there was an overall 17-, 22-, and 23-fold increase in saquinavir AUC(0,24 h) on day 14 with regimens E, F, and G, respectively (with confidence intervals of 10-30, 13-37, and 13-39). The lowest combination dose of RTV (200 : 800 mg; E) significantly increased the saquinavir AUC(0,24 h) from below 5 to 57 microg ml(-1) h, which was higher than the exposure obtained with the 400 : 400 mg twice daily regimen (i.e. 36 microg ml(-1) h). RTV also reduced intersubject variability in AUC(0,24 h) for saquinavir from 105% to 32-68%, and C(max)(0,24 h) from 124% to 30-49%. In contrast, SQV showed no clinically significant effect on the pharmacokinetics of ritonavir. The combination regimens were well tolerated, with the least number of adverse events recorded for the 200 : 800 mg (RTV : SQV) combination regimen.. RTV significantly increases saquinavir exposure as a consequence of inhibiting SQV metabolism and possibly P-glycoprotein efflux. Pharmacokinetic and safety profiles obtained in the current study indicate that the use of a combination with a lower dose of RTV and a higher dose of SQV than the 400 : 400 mg combination frequently used in clinical practice should be further explored.

Topics: Adolescent; Adult; Area Under Curve; Capsules; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Exanthema; Female; Gelatin; HIV Protease Inhibitors; Humans; Male; Middle Aged; Nausea; Patient Dropouts; Ritonavir; Saquinavir; Vomiting

In late 2019, a new coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-was discovered in Wuhan, China, and the World Health Organization later declared coronavirus disease 2019 (COVID-19) a pandemic. Numerous drugs have been repurposed and investigated for therapeutic effectiveness in the disease, including those from "Solidarity," an international clinical trial (azithromycin, chloroquine, hydroxychloroquine, the fixed combination lopinavir/ritonavir, and remdesivir).. Our objective was to evaluate adverse drug reaction (ADR) reporting for drugs when used in the treatment of COVID-19 compared with use for other indications, specifically focussing on sex differences.. We extracted reports on COVID-19-specific treatments from the global ADR database, VigiBase, using an algorithm developed to identify reports that listed COVID-19 as the indication. The Solidarity trial drugs were included, as were any drugs reported ≥ 100 times. We performed a descriptive comparison of reports for the same drugs used in non-COVID-19 indications. The data lock point date was 7 June 2020.. In total, 2573 reports were identified for drugs used in the treatment of COVID-19. In order of frequency, the most reported ADRs were electrocardiogram QT-prolonged, diarrhoea, nausea, hepatitis, and vomiting in males and diarrhoea, electrocardiogram QT-prolonged, nausea, vomiting, and upper abdominal pain in females. Other hepatic and kidney-related events were included in the top ten ADRs in males, whereas no hepatic or renal terms were reported for females. COVID-19-related reporting patterns differed from non-pandemic reporting for these drugs.. Review of a global database of suspected ADR reports revealed sex differences in the reporting patterns for drugs used in the treatment of COVID-19. Patterns of ADR sex differences need further elucidation.

Topics: Abdominal Pain; Adenosine Monophosphate; Alanine; Antibodies, Monoclonal, Humanized; Antiviral Agents; Azithromycin; Chemical and Drug Induced Liver Injury; Chloroquine; COVID-19 Drug Treatment; Databases, Pharmaceutical; Diarrhea; Drug Combinations; Drug Eruptions; Drug Repositioning; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; Male; Nausea; Oseltamivir; Ritonavir; Sex Distribution; Sex Factors; Vomiting

Ritonavir, a protease inhibitor drug, is commonly used in AIDS therapy. As with other chemotherapeutic drugs that cause gastrointestinal adverse effects, ritonavir treatment is associated with significant nausea and vomiting. This study investigated whether Scutellaria baicalensis, and its active flavonoid constituent, baicalein, attenuate the gastrointestinal effects of ritonavir. The effects of herb administration were evaluated in ritonavir-treated rats using a rat pica model, which simulates nausea and vomiting in humans. The effects of herb administration on gastric emptying in rats were also measured. Ritonavir treatment resulted in increased kaolin intake or severe pica, the intensity of which was reduced significantly with S. baicalensis administration (1 mg kg(-1); P<0.05). High-performance liquid chromatography analysis of S. baicalensis showed the presence of an extremely potent flavonoid constituent, baicalein. The study aimed to determine if baicalein contributed to the anti-pica effect of the extract. It was observed that baicalein dose-dependently decreased pica in ritonavir-treated rats (P<0.001). In addition to inducing pica, ritonavir also significantly delayed gastric emptying, which could contribute to ritonavir-induced gastrointestinal dysfunction. When S. baicalensis extract was administered to ritonavir-treated rats the delayed gastric emptying was significantly attenuated (P<0.05). The results suggest that S. baicalensis and the constituent baicalein reduce the gastrointestinal dysfunction caused by ritonavir. It is concluded that S. baicalensis may potentially have a role to play in reducing drug-induced adverse effects.

Topics: Animals; Antiemetics; Antioxidants; Disease Models, Animal; Dose-Response Relationship, Drug; Flavanones; Flavonoids; Gastric Emptying; HIV Protease Inhibitors; Kaolin; Male; Nausea; Pica; Plant Extracts; Plant Roots; Rats; Rats, Wistar; Ritonavir; Scutellaria baicalensis; Vomiting

Ritonavir (RTV), a protease inhibitor, and carbamazepine (CBZ), an anticonvulsant, were administered concurrently to a patient who had human immunodeficiency virus infection and epilepsy. The combination resulted in elevated serum concentrations of CBZ, with accompanying vomiting, vertigo, and transient liver dysfunction. After discontinuing RTV and reducing the dosage of CBZ, the serum concentration of CBZ returned to the optimal range, symptoms subsided, and liver function returned to baseline. Carbamazepine is metabolized in the liver to a large extent by the cytochrome P450 (CYP) system, especially CYP3A4, 2C8, and 1A2, whereas RTV is metabolized primarily by CYP3A and is a potent inhibitor of this enzyme. Careful clinical monitoring may help prevent adverse drug interactions when these drugs are administered concurrently.

Topics: Adult; Anti-HIV Agents; Anticonvulsants; Carbamazepine; Chemical and Drug Induced Liver Injury; Drug Interactions; Humans; Male; Ritonavir; Vertigo; Vomiting

A retrospective study was performed to determine whether twice-daily ritonavir 400 mg plus twice-daily saquinavir 400 mg (ritonavir 400/saquinavir 400) was better tolerated than ritonavir 600 mg twice daily (ritonavir 600). A secondary objective was to determine whether the rate of discontinuation due to therapeutic failure differed between the two ritonavir regimens.. The study was a retrospective chart review. Data collected included ritonavir dose; length of ritonavir therapy; reason for discontinuation; HIV-1 RNA prior to and at discontinuation of ritonavir therapy; CD4+ count; and antiretroviral therapy prior to, concomitant with, and initiated after ritonavir therapy.. Patient charts were reviewed in a university teaching hospital clinic.. Patients were identified through a search of the pharmacy database from December 18, 1995, to December 18, 1997. Patients were > 18 years old, but not restricted by gender or race.. The main outcome measures were frequency of discontinuation of ritonavir due to intolerance or due to lack of therapeutic efficacy.. The search identified 116 patients, including 57 patients taking ritonavir 400/saquinavir 400 and 54 patients taking ritonavir 600. Five patients on other ritonavir regimens were excluded. Significantly fewer patients receiving ritonavir 400/saquinavir 400 (14%) discontinued ritonavir due to intolerance compared with ritonavir 600 (37%; p = 0.002). Discontinuations due to therapeutic failure were not significantly different: 8.8% for ritonavir 400/saquinavir 400 and 7.4% for ritonavir 600, despite the fact that ritonavir/saquinavir therapy followed another protease inhibitor in 41 patients (73.2%) compared with 12 patients (24.5%) for ritonavir 600 (p = 0.001).. Ritonavir 400/saquinavir 400 is better tolerated than ritonavir 600.

Topics: Adult; Anti-HIV Agents; Diarrhea; Dose-Response Relationship, Drug; Drug Evaluation; Drug Therapy; Drug Therapy, Combination; Female; Gastrointestinal Diseases; HIV Infections; Humans; Male; Middle Aged; Nausea; Protease Inhibitors; Retrospective Studies; Ritonavir; Saquinavir; Treatment Outcome; Vomiting