ABSTRACT
BACKGROUND: Intranasal esketamine is an approved drug for treatmentresistant depression (TRD); however, it is costly and may result in specific adverse effects. In this single case study, we explored if oral esketamine can be a suitable alternative. METHODS: In collaboration with a 39yearold female with TRD, we compared plasma concentration curves of intranasal (84 mg) and oral (1, 2 and 4 mg/kg) esketamine. Because oral esketamine has a relatively low bioavailability, it results in a different ratio between esketamine and its primary metabolite noresketamine. To increase the bioavailability of oral esketamine, we coadministered a single dose of the cytochrome P450 (CYP) 3A4 inhibitor cobicistat (150 mg). RESULTS: For all doses administered, oral esketamine resulted in lower esketamine but higher noresketamine peak plasma concentrations compared with intranasal treatment. Using oral esketamine it was not possible to generate a similar esketamine plasma concentration curve as with the intranasal treatment, except when combined with cobicistat (esketamine 2 mg/kg plus cobicistat 150 mg). CONCLUSIONS: Our findings demonstrate that cobicistat effectively increases the bioavailability of oral esketamine. Further research is required in a larger population, especially to investigate the clinical benefit of cobicistat as a booster drug for oral esketamine.
Subject(s)
Administration, Intranasal , Biological Availability , Cobicistat , Depressive Disorder, Treatment-Resistant , Ketamine , Ketamine/administration & dosage , Ketamine/pharmacokinetics , Female , Humans , Adult , Administration, Oral , Cobicistat/administration & dosage , Cobicistat/pharmacokinetics , Depressive Disorder, Treatment-Resistant/drug therapy , Antidepressive Agents/administration & dosage , Antidepressive Agents/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Drug InteractionsABSTRACT
BACKGROUND: Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the potential to reduce PK variability and financial burden. The aim of this study was to investigate equivalence of a boosted, reduced dose of olaparib compared to the non-boosted standard dose. METHODS: This cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted with the strong CYP3A-inhibitor cobicistat 150 mg BID. Patients were randomised to the standard therapy followed by the boosted therapy, or vice versa. After seven days of each therapy, dense PK sampling was performed for noncompartmental PK analysis. Equivalence was defined as a 90% Confidence Interval (CI) of the geometric mean ratio (GMR) of the boosted versus standard therapy area under the plasma concentration-time curve (AUC0-12 h) within no-effect boundaries. These boundaries were set at 0.57-1.25, based on previous pharmacokinetic studies with olaparib capsules and tablets. RESULTS: Of 15 included patients, 12 were eligible for PK analysis. The GMR of the AUC0-12 h was 1.45 (90% CI 1.27-1.65). No grade ≥3 adverse events were reported during the study. CONCLUSIONS: Boosting a 100 mg BID olaparib dose with cobicistat increases olaparib exposure 1.45-fold, compared to the standard dose of 300 mg BID. Equivalence of the boosted olaparib was thus not established. Boosting remains a promising strategy to reduce the olaparib dose as cobicistat increases olaparib exposure Adequate tolerability of the boosted therapy with higher exposure should be established.
Subject(s)
Cytochrome P-450 CYP3A , Piperazines , Humans , Cross-Over Studies , Piperazines/therapeutic use , Cobicistat/pharmacokineticsABSTRACT
INTRODUCTION: Exposure to osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treatment of non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation, can be substantially below average. We evaluated whether plasma levels could be boosted by co-administration of cobicistat, a strong Cytochrome P450 3A-inhibitor. METHODS: This was a pharmacokinetic, proof-of-concept clinical trial (the OSIBOOST trial, NCT03858491). NSCLC-patients with osimertinib were eligible if their steady state osimertinib plasma trough concentration was low (≤195 ng/mL). On day 1, the area under the plasma curve (AUC0-24,ss) of osimertinib and its metabolite (AZ5104) was calculated using a limited sampling strategy (four samples). Cobicistat co-treatment (150 mg, once daily) was started on day 2. Between day 22-26, a second AUC was determined. Cobicistat dose could be escalated if the osimertinib trough concentration was still ≤ 195 ng/mL, in the absence of toxicity. Primary endpoint was the increase in osimertinib exposure, secondary endpoint was toxicity. Cobicistat could be continued during the expanded access phase, with follow-up (2-4 months) of the boosting effect. RESULTS: The mean baseline osimertinib trough concentration for the eleven enrolled patients was 154 ng/mL. In all patients, cobicistat addition led to an increase in osimertinib exposure. Mean increase in total AUC0-24ss (AUC osimertinib + AUC AZ5104) was 60%, (range 19%-192%). The boosting effect was consistent over time. No grade ≥ 2 toxicity was observed. CONCLUSION: Pharmacokinetic boosting of osimertinib with cobicistat in patients with NSCLC is feasible without increasing toxicity, although the degree of boosting is variable.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Protein Kinase Inhibitors , Acrylamides/pharmacokinetics , Aniline Compounds/therapeutic use , Antineoplastic Agents/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Cobicistat/pharmacokinetics , ErbB Receptors/genetics , Humans , Indoles , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation/genetics , Proof of Concept Study , Protein Kinase Inhibitors/pharmacokinetics , PyrimidinesABSTRACT
Fostemsavir is a prodrug of temsavir, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells with demonstrated efficacy in phase 2 and 3. Temsavir is a P-glycoprotein and breast cancer resistance protein (BCRP) substrate; its metabolism is mediated by esterase and CYP3A4 enzymes. Drugs that induce or inhibit CYP3A, P-glycoprotein, and BCRP may affect temsavir concentrations. Understanding potential drug-drug interactions (DDIs) following fostemsavir coadministration with antiretrovirals approved for HIV-1-infected treatment-experienced patients, including darunavir plus cobicistat (DRV/c) or DRV plus low-dose ritonavir (DRV/r) and etravirine, is clinically relevant. Open-label, single-sequence, multiple-dose, multicohort DDI studies were conducted in healthy participants (n = 46; n = 32). The primary objective was to assess the effects of DRV/r, etravirine, DRV/r plus etravirine, cobicistat, and DRV/c on temsavir systemic exposures; safety was a secondary objective. Compared with fostemsavir alone, coadministration with DRV/r increased the temsavir maximum observed plasma concentration (Cmax), area under the concentration-time curve in one dosing interval (AUCtau), and plasma trough concentration (Ctau) by 52%, 63%, and 88%, respectively, while etravirine decreased the temsavir Cmax, AUCtau, and Ctau by â¼50% each. DRV/r plus etravirine increased the temsavir Cmax, AUCtau, and Ctau by 53%, 34%, and 33%, respectively. Compared with fostemsavir alone, coadministration with cobicistat increased the temsavir Cmax, AUCtau, and Ctau by 71%, 93%, and 136%, respectively; DRV/c increased the temsavir Cmax, AUCtau, and Ctau by 79%, 97%, and 124%, respectively. Fostemsavir with all combinations was generally well tolerated. No dose adjustment is required for fostemsavir when coadministered with strong CYP3A inhibitors, P-glycoprotein inhibitors, and modest inducers, including regimens with DRV/r, DRV/c, cobicistat, etravirine, and DRV/r plus etravirine based on the therapeutic margin for temsavir (ClinicalTrials.gov registration no. NCT02063360 and NCT02277600).
Subject(s)
Anti-HIV Agents , HIV Infections , HIV-1 , Prodrugs , ATP Binding Cassette Transporter, Subfamily B, Member 1 , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Anti-HIV Agents/therapeutic use , Clinical Studies as Topic , Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , HIV Infections/drug therapy , Healthy Volunteers , Humans , Neoplasm Proteins , Nitriles , Organophosphates , Piperazines , Prodrugs/pharmacology , Pyrimidines , RitonavirABSTRACT
BACKGROUND: Bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination (BIC/FTC/TAF 50/200/25 mg) is recommended as an initial regimen in patients who are antiretroviral (ARV)-naïve or virologically suppressed on a stable ARV regimen. However, no real-world pharmacokinetic (PK) data are available in treatment-experienced patients with antiretroviral resistance receiving BIC/FTC/TAF plus a boosted protease inhibitor. SETTING/METHODS: This prospective, single-center, nonrandomized pharmacokinetic study enrolled adult treatment-experienced persons with HIV and creatinine clearance >30 mL/min receiving BIC/FTC/TAF + DRV/c as part of routine clinical care. Steady-state PK profiles of BIC, TAF, tenofovir (TFV), and DRV after daily dosing of BIC/FTC/TAF + darunavir/cobicistat (DRV/c) were obtained with samples at predose and 0.5, 1, 2, and 4 hours postdose. The AUC0-24 at steady state was extrapolated by imputing C0 for C24 for each participant (AUC0-tau,exp). RESULTS: Nine participants were enrolled with a median age of 59 years (range 54-67) and median number of years on ART of 19 (range 5.8-30). The median (interquartile range [IQR]) BIC AUC0-tau,exp and Cmax values were 128.9 µg*h/mL (78.1-159.5) and 6.9 µg/mL (5.1-9.8), respectively. The median (IQR) TAF AUC0-tau,exp and Cmax values were 0.376 µg*h/mL (0.199-0.430) and 0.276 µg/mL (0.149-0.543), respectively. Predose concentrations of TFV and DRV were comparable with historical data. CONCLUSION: Treatment-experienced persons with HIV receiving BIC/FTC/TAF + darunavir/cobicistat (DRV/c) had BIC exposures (AUC0-tau) that were increased by approximately 26% compared with historical PK data. Although TAF exposures were substantially increased, plasma TFV was only modestly higher. These results suggest that BIC/TAF/FTC + DRV/c is a viable antiviral regimen option for treatment-experienced persons.
Subject(s)
Amides/pharmacokinetics , Anti-HIV Agents/pharmacokinetics , Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , HIV Infections/drug therapy , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Piperazines/pharmacokinetics , Pyridones/pharmacokinetics , Tenofovir/pharmacokinetics , Aged , Amides/blood , Anti-HIV Agents/blood , Antiretroviral Therapy, Highly Active/methods , Chromatography, Liquid , Cobicistat/blood , Darunavir/blood , Female , Heterocyclic Compounds, 3-Ring/blood , Humans , Male , Middle Aged , Piperazines/blood , Prospective Studies , Pyridones/blood , Tandem Mass Spectrometry , Tenofovir/bloodABSTRACT
The single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg has undergone phase III studies AMBER (NCT02431247) and EMERALD (NCT02269917) in HIV-infected patients. An existing population pharmacokinetic (PopPK) model for cobicistat-boosted darunavir (DRV) was updated to describe DRV PK in AMBER and EMERALD. For TAF, a PopPK model was developed using richly sampled phase I/II data and updated with sparsely sampled AMBER data. Individual exposure metrics for DRV and TAF in patients receiving D/C/F/TAF were derived (AMBER, n=356; EMERALD, n=750). The DRV PopPK model is a two-compartment model with sequential zero-order, first-order input. TAF PK is described by a one-compartment model with dual parallel input for absorption (slow and fast pathway). DRV covariates were α1-acid-glycoprotein and body weight. TAF covariates were lean body weight and α1-acid-glycoprotein. DRV and TAF PK were unaffected by age, race, or gender. Estimated DRV mean (SD) C0h and AUC24h, respectively, were 1899 (759) ng/mL and 87,909 (20,232) ng*h/mL in AMBER; 1813 (859) ng/mL and 85,972 (22,413) ng*h/mL in EMERALD. Estimated TAF mean (SD) AUC24h was 132 (41) ng*h/mL. These PK parameters were in line with historical data. No apparent relationships of DRV or TAF exposure with efficacy (virologic response) or safety (metabolic, cardiac, liver, gastrointestinal, skin, bone, renal, pancreas, lipid events) parameters were seen. Additionally, our findings demonstrate that in patients with low plasma concentrations, there is no risk of decreased virologic response or virologic rebound. This supports the use of a once-daily, single-tablet regimen of D/C/F/TAF 800/150/200/10 mg for the treatment of HIV-1-infected subjects.
Subject(s)
Alanine/pharmacokinetics , Anti-HIV Agents/pharmacokinetics , Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , Emtricitabine/pharmacokinetics , HIV Infections/drug therapy , Tenofovir/analogs & derivatives , Adult , Aged , Alanine/administration & dosage , Alanine/adverse effects , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Biological Variation, Population , Cobicistat/administration & dosage , Cobicistat/adverse effects , Darunavir/administration & dosage , Darunavir/adverse effects , Drug Combinations , Emtricitabine/administration & dosage , Emtricitabine/adverse effects , Female , HIV Infections/blood , HIV Infections/diagnosis , HIV Infections/virology , HIV-1/drug effects , HIV-1/isolation & purification , Humans , Male , Middle Aged , Tablets , Tenofovir/administration & dosage , Tenofovir/adverse effects , Tenofovir/pharmacokinetics , Treatment Outcome , Viral Load/drug effects , Young AdultABSTRACT
Bictegravir is equally metabolized by cytochrome P450 (CYP)3A and uridine diphosphate-glucuronosyltransferase (UGT)1A1. Drug-drug interaction (DDI) studies were only conducted for strong inhibitors and inducers, leading to some uncertainty whether moderate perpetrators or multiple drug associations can be safely coadministered with bictegravir. We used physiologically-based pharmacokinetic (PBPK) modeling to simulate DDI magnitudes of various scenarios to guide the clinical DDI management of bictegravir. Clinically observed DDI data for bictegravir coadministered with voriconazole, darunavir/cobicistat, atazanavir/cobicistat, and rifampicin were predicted within the 95% confidence interval of the PBPK model simulations. The area under the curve (AUC) ratio of the DDI divided by the control scenario was always predicted within 1.25-fold of the clinically observed data, demonstrating the predictive capability of the used modeling approach. After the successful verification, various DDI scenarios with drug pairs and multiple concomitant drugs were simulated to analyze their effect on bictegravir exposure. Generally, our simulation results suggest that bictegravir should not be coadministered with strong CYP3A and UGT1A1 inhibitors and inducers (e.g., atazanavir, nilotinib, and rifampicin), but based on the present modeling results, bictegravir could be administered with moderate dual perpetrators (e.g., efavirenz). Importantly, the inducing effect of rifampicin on bictegravir was predicted to be reversed with the concomitant administration of a strong inhibitor such as ritonavir, resulting in a DDI magnitude within the efficacy and safety margin for bictegravir (0.5-2.4-fold). In conclusion, the PBPK modeling strategy can effectively be used to guide the clinical management of DDIs for novel drugs with limited clinical experience, such as bictegravir.
Subject(s)
Amides/pharmacokinetics , Cytochrome P-450 CYP3A Inducers/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Drug Interactions/physiology , Glucuronosyltransferase/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Models, Biological , Piperazines/pharmacokinetics , Pyridones/pharmacokinetics , Adult , Cobicistat/pharmacokinetics , Female , Humans , Male , Middle Aged , Ritonavir/pharmacokinetics , Voriconazole/pharmacokinetics , Young AdultABSTRACT
Drug-drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in people living with HIV, particularly in those with impaired renal function, because they can result in increased dabigatran exposure and thus an increased risk of major bleeding events. However, the extent of this interaction and subsequent need for dose adjustment in subjects with varying degrees of renal function is currently not yet fully understood. To close this knowledge gap, we conducted an integrated population physiologically-based pharmacokinetic/pharmacodynamic analysis linking changes in dabigatran exposure due to DDIs and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within 1 year. The results of our analysis suggest that coadministration of dabigatran etexilate (dabigatran prodrug) and ritonavir/cobicistat should be avoided in subjects with severe renal impairment. A 2-hour dose separation or dabigatran etexilate dose reduction to 110 mg b.i.d. (twice daily) should be considered in subjects with moderate renal impairment when coadministered with ritonavir, while the dabigatran etexilate dose should be further reduced to 75 mg b.i.d. when coadministered with cobicistat. No dabigatran etexilate dose adjustment is needed in subjects with normal renal function receiving ritonavir, but dabigatran etexilate dose reduction to 110 mg b.i.d. should be considered when coadministered with cobicistat.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/metabolism , Dabigatran/administration & dosage , Dabigatran/pharmacokinetics , Drug Interactions/physiology , Kidney Diseases/drug therapy , Area Under Curve , Cobicistat/pharmacokinetics , Hemorrhage/chemically induced , Humans , Kidney Diseases/metabolism , Risk Assessment , Ritonavir/administration & dosage , Ritonavir/pharmacokineticsABSTRACT
The inhibitor of anaplastic lymphoma kinase (ALK) crizotinib significantly increases survival in patients with ALK-positive non-small cell lung cancer (NSCLC). When evaluating crizotinib pharmacokinetics (PKs) in patients taking the standard flat oral dose of 250 mg b.i.d., interindividual PK variability is substantial and patient survival is lower in the quartile with the lowest steady-state trough plasma concentrations (Cmin,ss ), suggesting that concentrations should be monitored and doses individualized. We investigated whether the CYP3A inhibitor cobicistat increases Cmin,ss of the CYP3A substrate crizotinib in patients with low exposure. Patients with ALK-positive NSCLC of our outpatient clinic treated with crizotinib were enrolled in a phase I trial (EudraCT 2016-002187-14, DRKS00012360) if crizotinib Cmin,ss was below 310 ng/mL and treated with cobicistat for 14 days. Crizotinib plasma concentration profiles were established before and after a 14-day co-administration of cobicistat to construct the area under the plasma concentration-time curve in the dosing interval from zero to 12 hours (AUC0-12 ). Patients were also monitored for adverse events by physical examination, laboratory tests, and 12-lead echocardiogram. Enrolment was prematurely stopped because of the approval of alectinib, a next-generation ALK-inhibitor with superior efficacy. In the only patient enrolled, cobicistat increased Cmin,ss from 158 ng/mL (before cobicistat) to 308 ng/mL (day 8) and 417 ng/mL (day 14 on cobicistat), concurrently the AUC0-12 increased by 78% from 2,210 ng/mL*h to 3,925 ng/mL*h. Neither safety signals nor serious adverse events occurred. Pharmacoenhancement with cobicistat as an alternative for dose individualisation for patients with NSCLC with low crizotinib exposure appears to be safe and is cost-effective and feasible.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Cobicistat/pharmacokinetics , Crizotinib/pharmacokinetics , Lung Neoplasms/drug therapy , Adult , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Anaplastic Lymphoma Kinase/genetics , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/economics , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Cobicistat/administration & dosage , Cobicistat/economics , Cost-Benefit Analysis , Crizotinib/administration & dosage , Crizotinib/economics , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/economics , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Dose-Response Relationship, Drug , Drug Synergism , Feasibility Studies , Female , Humans , Lung Neoplasms/blood , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Male , Middle Aged , Mutation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/economics , Protein Kinase Inhibitors/pharmacokineticsABSTRACT
No disponible
Subject(s)
Humans , Coronavirus Infections/drug therapy , Severe acute respiratory syndrome-related coronavirus/pathogenicity , Lopinavir/pharmacokinetics , Ritonavir/pharmacokinetics , Acute Chest Syndrome/drug therapy , Darunavir/pharmacokinetics , Cobicistat/pharmacokinetics , Decision Making , Policy Making , Pandemics/prevention & controlABSTRACT
BACKGROUND: The potential for clinically significant drug interactions (CSDIs) for patients taking ritonavir and cobicistat is high because of their powerful pharmacokinetic effect on the cytochrome P450 (CYP) enzyme system, most notably their inhibitory effect on CYP3A4. AIMS: An audit was conducted to measure and correct for patients exposed to potentially dangerous drug interactions. METHODS: Two hundred individuals attending a regional specialist human immunodeficiency virus (HIV) clinic between June and September 2014 who were receiving the pharmacokinetic enhancers ritonavir or cobicistat were interviewed to determine a medication history including medications prescribed by their general practitioner (GP), over-the-counter (OTC) medicines, herbal remedies and recreational drugs. RESULTS: Of the 200 patients interviewed, patients were aged 23-76 years (median age was 41.5), 64% were female and 173 reported taking a co-medication. Sixty-six (33%) were taking a medication or medications which had no significant drug interaction associated with them. One hundred and seven (54%) were taking one or more medications with a CSDI which could require a dose adjustment, close monitoring or an absolute contraindication. Only 27% of these co-medications were identified in the normal course of an outpatient visit outside of the audit. CONCLUSION: A detailed medication history is often lacking at routine HIV follow-up visits. There is a significant risk of CSDIs in this cohort. Awareness of physicians and pharmacists needs to be raised. Implementation of several innovative strategies to capture the most accurate medication histories and avoid drug toxicities now employed in this cohort is also discussed here.
Subject(s)
Anti-HIV Agents/therapeutic use , Ritonavir/therapeutic use , Adult , Aged , Anti-HIV Agents/pharmacokinetics , Cobicistat/pharmacokinetics , Cobicistat/therapeutic use , Drug Interactions , Female , Humans , Male , Middle Aged , Ritonavir/pharmacokinetics , Young AdultABSTRACT
Introduction: Ritonavir and cobicistat are pharmacoenhancers used to improve the disposition of other HIV antiretrovirals. These drugs are, however, characterized by important pharmacokinetic differences.Areas covered: Here, the authors firstly update the available information on the pharmacokinetics of ritonavir and cobicistat. Subsequently, the review focuses on the description of drug-drug interactions (DDIs) involving cobicistat and comedications that might beneficiate from a shift-back to ritonavir. A MEDLINE Pubmed search for articles published from January 1995 to April 2019 was completed matching the term ritonavir or cobicistat with pharmacokinetics, DDIs, and pharmacology. Moreover, additional studies were identified from the reference list of retrieved articles.Expert opinion: Despite more than 20 years after its introduction on the market, ritonavir still represents a valid option for the treatment of selected HIV-infected patients. The large-scale switch to cobicistat may result in some unexpected DDIs not previously reported for ritonavir. Besides the issue of DDIs, additional advantage of ritonavir over cobicistat is its use in pregnancy, and its availability as single component of pharmaceutical formulations allowing the fine-tuning of antiretroviral regimens in patients with heavy polypharmacy when other unboosted-based therapeutic options cannot be used.
Subject(s)
Anti-HIV Agents/administration & dosage , Cobicistat/administration & dosage , Ritonavir/administration & dosage , Anti-HIV Agents/pharmacokinetics , Cobicistat/pharmacokinetics , Drug Interactions , Drug Therapy, Combination , HIV Infections/drug therapy , Humans , Ritonavir/pharmacokineticsABSTRACT
Treatment of individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) requires careful consideration of potential drug-drug interactions. The pharmacokinetic interaction of the HCV fixed-dose combination treatment of elbasvir/grazoprevir (EBR/GZR) when coadministered with the fixed-dose combination HIV treatment of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (EVG/COB/TDF/FTC) was evaluated in 22 healthy adults. In period 1, oral doses of EVG/COB/TDF/FTC (150 mg/150 mg/300 mg/200 mg) were administered once daily for 7 days. In period 2, oral doses of EBR/GZR (50 mg/100 mg) were administered once daily for 10 days. In period 3, oral doses of EVG/COB/TDF/FTC were coadministered with EBR/GZR once daily for 10 days. The pharmacokinetics of EVG/COB/TDF/FTC were not clinically meaningfully altered by concomitant EBR/GZR administration. Geometric mean ratios (90%CIs) for area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24 ) in the presence/absence of EBR/GZR were 1.1 (1.0, 1.2) for elvitegravir; 1.1 (1.0, 1.1) for emtricitabine; 1.2 (1.1, 1.2) for tenofovir; and 1.5 (1.4, 1.6) for cobicistat. In comparison, the AUC0-24 of elbasvir was â¼2 times higher and the AUC0-24 of grazoprevir was â¼5 times higher following concomitant administration of EVG/COB/TDF/FTC and EBR/GZR. Geometric mean ratios (90%CI) for AUC0-24 in the presence/absence of EVG/COB/TDF/FTC were 2.2 (2.0, 2.4) for elbasvir and 5.4 (4.5, 6.4) for grazoprevir. Coadministration of EVG/COB/TDF/FTC and EBR/GZR was generally well tolerated in healthy adults in this study. Nevertheless, because of the increased GZR exposure that occurs with coadministration of EVG/COB/TDF/FTC and EBR/GZR, coadministration of this combination is not recommended in those coinfected with HIV and HCV.
Subject(s)
Benzofurans/pharmacokinetics , Cobicistat/pharmacokinetics , Emtricitabine/pharmacokinetics , Imidazoles/pharmacokinetics , Quinolones/pharmacokinetics , Quinoxalines/pharmacokinetics , Tenofovir/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , Benzofurans/administration & dosage , Cobicistat/administration & dosage , Drug Administration Schedule , Drug Combinations , Drug Interactions , Emtricitabine/administration & dosage , Female , Healthy Volunteers , Humans , Imidazoles/administration & dosage , Male , Middle Aged , Quinolones/administration & dosage , Quinoxalines/administration & dosage , Tenofovir/administration & dosageABSTRACT
: Product labels for cobicistat with atazanavir or darunavir, and for elvitegravir/cobicistat/emtricitabine/tenofovir (alafenamide or disoproxil fumarate) were recently updated to state that these products are not recommended for initiation during pregnancy, and an alternative regimen is recommended for those who become pregnant during therapy with these products. Herein, we present the rationale for these recommendations, which are based on studies in pregnant women evaluating the pharmacokinetics and antiviral activity of darunavir/cobicistat or elvitegravir/cobicistat-containing antiretroviral regimens. In these studies, mean steady-state minimum concentrations in the second and third trimester versus postpartum of cobicistat, darunavir, and elvitegravir were reduced by 61-83%, 89-92%, and 82-86%, respectively. In the absence of data with atazanavir/cobicistat, we leveraged the available data with darunavir/cobicistat and elvitegravir/cobicistat to make recommendations for atazanavir/cobicistat. Darunavir/ritonavir and atazanavir/ritonavir remain viable treatment options for pregnant women.
Subject(s)
Anti-HIV Agents/administration & dosage , Anti-HIV Agents/pharmacokinetics , Antiretroviral Therapy, Highly Active/methods , Cobicistat/administration & dosage , Cobicistat/pharmacokinetics , HIV Infections/drug therapy , Pregnancy Complications, Infectious/drug therapy , Female , Humans , Pregnancy , Treatment OutcomeABSTRACT
OBJECTIVES: The aim of the study was to evaluate darunavir and cobicistat pharmacokinetics in pregnant women with HIV-1 infection. METHODS: This phase 3b, open-label study enrolled HIV-1-infected pregnant women (18-26 weeks of gestation) receiving combination antiretroviral therapy with once-daily darunavir/cobicistat 800/150 mg. The plasma pharmacokinetics of darunavir (total and unbound) and cobicistat were assessed over 24 h during the second and third trimesters (24-28 and 34-38 weeks of gestation, respectively) and 6-12 weeks postpartum. Pharmacokinetic parameters [area under the plasma concentration-time curve over 24 h (AUC24 h ), maximum plasma concentration (Cmax ) and minimum plasma concentration (Cmin )] were derived using noncompartmental analysis and compared using linear mixed effects modelling (pregnancy versus postpartum). Antiviral activity and safety were evaluated. RESULTS: Seven women were enrolled in the study; six completed it. Total darunavir exposure was lower during pregnancy than postpartum (AUC24 h , 50-56% lower; Cmax , 37-49% lower; Cmin , 89-92% lower); unbound darunavir exposure was also reduced (AUC24 h , 40-45% lower; Cmax , 32-41% lower; Cmin , 88-92% lower). Cobicistat exposure was also lower during pregnancy than postpartum (AUC24 h , 49-63% lower; Cmax , 27-50% lower; Cmin , 83% lower). At study completion, five of six (83%) women were virologically suppressed (HIV-1 RNA < 50 copies/mL). There was one virological failure (the patient was nonadherent; no emerging genotypic resistance was observed and susceptibility to antiretrovirals was maintained). No mother-to-child transmission was detected among six infants born to the six women who completed the study. Overall, darunavir/cobicistat was well tolerated in women and infants. CONCLUSIONS: In view of markedly reduced darunavir and cobicistat exposures during pregnancy, this combination is not recommended in HIV-1-infected pregnant women.
Subject(s)
Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , HIV Infections/drug therapy , Pregnancy Complications, Infectious/drug therapy , Adult , Cobicistat/administration & dosage , Darunavir/administration & dosage , Drug Therapy, Combination , Female , Gestational Age , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical/statistics & numerical data , Maternal Age , Postpartum Period/blood , Pregnancy , Pregnancy Trimester, Second/blood , Treatment OutcomeABSTRACT
The effect of food on the bioavailability of the components of the once-daily, single-tablet human immunodeficiency virus (HIV) type 1 regimen containing darunavir (DRV 800 mg), cobicistat (COBI 150 mg), emtricitabine (FTC 200 mg), and tenofovir alafenamide (TAF 10 mg) (D/C/F/TAF) (NCT02475135) and the bioequivalence of D/C/F/TAF versus combined intake of the separate agents (NCT02578550) were evaluated. These were 2 phase 1, open-label, randomized, 2-period crossover studies (7-day washout between treatments) in HIV-negative healthy volunteers. Twenty-four participants each received a single dose of D/C/F/TAF in fasted conditions (test) or after a standardized high-fat breakfast (reference). Ninety-six participants each received a single dose of D/C/F/TAF (test) or combined intake of a single DRV 800-mg tablet, a COBI 150-mg tablet, and an FTC/TAF 200/10-mg tablet (reference), both after a standardized regular-calorie, regular-fat breakfast. Pharmacokinetic profiles for all D/C/F/TAF components, safety, and tolerability were assessed. Following D/C/F/TAF in fasted conditions, DRV peak concentration, area under the concentration-time curve from time of administration until the last time point with a measurable concentration (AUC)last , and extrapolated to infinity (AUCinf ) were lower by 45%, 34%, and 30%, respectively, compared with fed conditions, with no clinically relevant differences in COBI, FTC, or TAF exposures between fed and fasted conditions. In the bioequivalence study 90% confidence intervals of the geometric mean ratios of all main pharmacokinetic parameters were within the 80.00% to 125.00% bioequivalence limits for DRV, COBI, FTC, and TAF. No grade 3/4 adverse events (AEs), serious AEs, deaths, or discontinuations due to AEs occurred. D/C/F/TAF is bioequivalent to combined administration of the separate agents. Consistent with other (co)formulations of DRV, DRV exposure was lower in fasted than in fed conditions as evaluated when taken with food, so D/C/F/TAF should be taken with food.
Subject(s)
Adenine/analogs & derivatives , Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , Fasting/blood , Adenine/administration & dosage , Adenine/pharmacokinetics , Adult , Alanine , Area Under Curve , Biological Availability , Cobicistat/administration & dosage , Cross-Over Studies , Darunavir/administration & dosage , Drug Combinations , Female , Food , Humans , Male , Middle Aged , Tablets , Tenofovir/analogs & derivatives , Therapeutic Equivalency , Young AdultABSTRACT
Background: Dolutegravir combined with darunavir/cobicistat is a promising NRTI-sparing and/or salvage strategy for the treatment of HIV-1 infection. Methods: This Phase I, open-label, 57 day, crossover, pharmacokinetic (PK) study, enrolled healthy volunteers aged 18-65 years, who were randomized to one of two groups. Group 1 received dolutegravir (50 mg) once daily for 14 days followed by a 7 day washout, then a 14 day dolutegravir/darunavir/cobicistat (DTG/DRV/COBI) once-daily co-administration period followed by a 7 day washout and finally a 14 day period of darunavir/cobicistat (800/150 mg) once daily. Group 2 followed the same sequence starting with darunavir/cobicistat and concluding with dolutegravir. Each group underwent intensive PK sampling over 24 h on day 14 of each drug period and DTG/DRV/COBI concentrations were measured using validated LC-MS/MS methods. Results: Twenty participants completed all PK phases. Thirteen were female and median age and BMI were 33.5 years and 27 kg/m2. Dolutegravir geometric mean ratios (GMR, DTG/DRV/COBI versus dolutegravir alone) and 90% CI for Cmax, AUC0-24 and C24 were 1.01 (0.92-1.11), 0.95 (0.87-1.04) and 0.9 (0.8-1.0), respectively. Darunavir GMR (DRV/COBI/DTG versus darunavir/cobicistat alone) and 90% CI for Cmax, AUC0-24 and C24 were 0.90 (0.83-0.98), 0.93 (0.86-1.00) and 0.93 (0.78-1.11), respectively. No grade 3 or 4 adverse events or laboratory abnormalities were observed. Conclusions: Concentrations of dolutegravir and darunavir, when boosted with cobicistat, decreased by <10% during co-administration, suggesting this combination can be prescribed safely in the treatment of HIV-1, with no adjustment to current guideline-recommended dosages.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Adolescent , Adult , Aged , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Cobicistat/administration & dosage , Cobicistat/adverse effects , Cross-Over Studies , Darunavir/administration & dosage , Darunavir/adverse effects , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Healthy Volunteers , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/adverse effects , Humans , Male , Middle Aged , Oxazines , Piperazines , Pyridones , Young AdultABSTRACT
Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is an oral once-daily single-tablet regimen for the treatment of human immunodeficiency virus-1 infection. Different administration modalities for the D/C/F/TAF fixed-dose combination tablet were explored in this phase 1 randomized, open-label, 3-period, 3-treatment crossover study enrolling 30 healthy adults. The primary objective was to assess the relative bioavailability of each component after a single dose of D/C/F/TAF (800/150/200/10 mg) administered as a split or crushed tablet (tests) versus swallowed whole (reference). Pharmacokinetic parameters (noncompartmental analysis; logarithm-transformed) for each component were compared using linear mixed-effects modeling. For the split versus whole tablet, the bioavailabilities (maximum plasma concentration [Cmax ] and area under the plasma concentration-time curve [AUClast ]) of each D/C/F/TAF component were comparable. For the crushed versus whole tablet, the bioavailabilities of darunavir, cobicistat, and emtricitabine were comparable, except for a 17% decrease in emtricitabine Cmax ; the relative bioavailability of tenofovir alafenamide decreased by 29% and 19% for Cmax and AUClast , respectively. All intakes were safe and generally well tolerated. In summary, there was no clinically relevant impact on the bioavailability of D/C/F/TAF components when administered as a split tablet compared with a tablet swallowed whole. Administration of a crushed tablet resulted in a modest decrease in tenofovir alafenamide bioavailability; the clinical relevance of this change has not been assessed but is expected to be minimal based on the wide therapeutic window for this agent.
Subject(s)
Adenine/analogs & derivatives , Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , Emtricitabine/pharmacokinetics , Adenine/administration & dosage , Adenine/pharmacokinetics , Adult , Alanine , Biological Availability , Cobicistat/administration & dosage , Cross-Over Studies , Darunavir/administration & dosage , Drug Combinations , Emtricitabine/administration & dosage , Female , Healthy Volunteers , Humans , Linear Models , Male , Middle Aged , Tablets , Tenofovir/analogs & derivatives , Young AdultABSTRACT
BACKGROUND: Cobicistat (COBI), a CYP3A inhibitor, is a pharmacokinetic enhancer that increases exposures of the HIV protease inhibitors (PIs) atazanavir (ATV) and darunavir (DRV). The potential drug interaction between COBI-boosted PIs and hormonal contraceptives, which are substrates of intestinal efflux transporters and extensively metabolized by CYP enzymes, glucuronidation and sulfation, was evaluated. METHODS: This was a Phase I, open-label, two cohort (n=18/cohort), fixed-sequence study in healthy females that evaluated the drug-drug interaction (DDI) between multiple-dose ATV+COBI or DRV+COBI and single-dose drospirenone/ethinyl estradiol (EE). DDIs were evaluated using 90% confidence intervals of the geometric least-squares mean ratios of the test (drospirenone/EE+boosted PI) versus reference (drospirenone/EE) using lack of DDI boundaries of 70-143%. Safety was assessed throughout the study. RESULTS: 29/36 participants completed the study. Relative to drospirenone/EE alone, drospirenone area under the plasma concentration versus time curve extrapolated to infinity (AUCinf) was 1.6-fold and 2.3-fold higher, and maximum observed plasma concentration (Cmax) was unaltered, upon coadministration with DRV+COBI and ATV+COBI, respectively. EE AUCinf decreased 30% with drospirenone/EE + DRV+COBI and was unchanged with ATV+COBI + drospirenone/EE, relative to drospirenone/EE alone. Study treatments were generally well tolerated. The majority of adverse events were mild and consistent with known safety profiles of the compounds. CONCLUSIONS: Consistent with COBI-mediated CYP3A inhibition, drospirenone exposure increased following coadministration with COBI-containing regimens, with a greater increase with ATV+COBI. Thus, clinical monitoring for drospirenone-associated hyperkalaemia is recommended with DRV+COBI and ATV+COBI should not be used with drospirenone. Lower EE exposure with DRV+COBI may be attributed to inductive effects of DRV on CYP enzymes and/or intestinal efflux transporters (that is, P-gp) involved in EE disposition.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , Cobicistat/pharmacokinetics , Cobicistat/therapeutic use , Ethinyl Estradiol/pharmacokinetics , Adolescent , Adult , Androstenes/administration & dosage , Androstenes/pharmacokinetics , Area Under Curve , Atazanavir Sulfate/pharmacokinetics , Atazanavir Sulfate/therapeutic use , Cohort Studies , Contraceptives, Oral, Hormonal , Darunavir/pharmacokinetics , Darunavir/therapeutic use , Drug Interactions , Ethinyl Estradiol/pharmacology , Female , Half-Life , Humans , Mineralocorticoid Receptor Antagonists/administration & dosage , Mineralocorticoid Receptor Antagonists/pharmacokinetics , Young AdultABSTRACT
OBJECTIVE: To evaluate elvitegravir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery. DESIGN: Nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and their children in the United States. METHODS: Intensive steady-state 24-h pharmacokinetic profiles after 150âmg of elvitegravir and 150âmg of cobicistat given orally in fixed dose combination once-daily were performed during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Elvitegravir and cobicistat were measured in plasma by a validated liquid chromatography with tandem mass spectrometry assay with a lower quantitation limit of 10âng/ml. A two-tailed Wilcoxon signed-rank test (αâ=â0.10) was employed for paired within-participant comparisons. RESULTS: Thirty pregnant women taking elvitegravir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, elvitegravir AUC0-24 was 24% lower in the second trimester [nâ=â14, Pâ=â0.058, geometric mean ratios (GMR)â=â0.76, 90% confidence interval (CI) 0.57-1.0] and 44% lower in the third trimester (nâ=â24, Pâ=â0.0001, GMRâ=â0.56, 90% CI 0.42-0.73), while cobicistat AUC0-24 was 44% lower in the second trimester (nâ=â14, Pâ=â0.0085, GMRâ=â0.56, 90% CI 0.37-0.85) and 59% lower in the third trimester (nâ=â24, Pâ<â0.0001, GMRâ=â0.41, 90% CI 0.30-0.57). Median cord blood elvitegravir concentration was 540.6âng/ml and the median ratio of cord blood to maternal plasma elvitegravir concentrations was 0.91. CONCLUSION: Standard elvitegravir and cobicistat dosing during pregnancy results in significantly lower exposure which may increase the risk of virologic failure and mother-to-child transmission. Additional studies are needed to optimize elvitegravir and cobicistat dosing regimens in pregnant women.