scholarly journals Lack of a Significant Drug Interaction between Raltegravir and Tenofovir

2008 ◽  
Vol 52 (9) ◽  
pp. 3253-3258 ◽  
Author(s):  
Larissa A. Wenning ◽  
Evan J. Friedman ◽  
James T. Kost ◽  
Sheila A. Breidinger ◽  
Jon E. Stek ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Peak Plasma ◽  
Geometric Mean ◽  
Integrase Inhibitor ◽  
Substantial Effect ◽  
Open Label ◽  
Time Curve ◽  
Once Daily ◽  
Hiv 1

ABSTRACT Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase inhibitor with potent in vitro activity (95% inhibitory concentration of 31 nM in 50% human serum). This article reports the results of an open-label, sequential, three-period study of healthy subjects. Period 1 involved raltegravir at 400 mg twice daily for 4 days, period 2 involved tenofovir disoproxil fumarate (TDF) at 300 mg once daily for 7 days, and period 3 involved raltegravir at 400 mg twice daily plus TDF at 300 mg once daily for 4 days. Pharmacokinetic profiles were also determined in HIV-1-infected patients dosed with raltegravir monotherapy versus raltegravir in combination with TDF and lamivudine. There was no clinically significant effect of TDF on raltegravir. The raltegravir area under the concentration time curve from 0 to 12 h (AUC0-12) and peak plasma drug concentration (C max) were modestly increased in healthy subjects (geometric mean ratios [GMRs], 1.49 and 1.64, respectively). There was no substantial effect of TDF on raltegravir concentration at 12 h postdose (C 12) in healthy subjects (GMR [TDF plus raltegravir-raltegravir alone], 1.03; 90% confidence interval [CI], 0.73 to 1.45), while a modest increase (GMR, 1.42; 90% CI, 0.89 to 2.28) was seen in HIV-1-infected patients. Raltegravir had no substantial effect on tenofovir pharmacokinetics: C 24, AUC, and C max GMRs were 0.87, 0.90, and 0.77, respectively. Coadministration of raltegravir and TDF does not change the pharmacokinetics of either drug to a clinically meaningful degree. Raltegravir and TDF may be coadministered without dose adjustments.

scholarly journals Evaluation of Doravirine Pharmacokinetics When Switching from Efavirenz to Doravirine in Healthy Subjects

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Ka Lai Yee ◽  
Rosa I. Sanchez ◽  
Patrice Auger ◽  
Rachael Liu ◽  
Li Fan ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Healthy Subjects ◽  
Geometric Mean ◽  
Transcriptase Inhibitor ◽  
Open Label ◽  
Genetic Barrier ◽  
Fixed Sequence ◽  
Time Curve ◽  
Cyp3a4 Substrate

ABSTRACT Doravirine is a novel, potent nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection that demonstrates a high genetic barrier to resistance and that has been well tolerated in studies to date. Doravirine is a candidate for patients switching from less-well-tolerated NNRTIs, such as efavirenz. While doravirine is a cytochrome P450 3A4 (CYP3A4) substrate, efavirenz induces CYP3A4; therefore, the pharmacokinetics of both drugs following a switch from efavirenz to doravirine were assessed. This was a 3-period, fixed-sequence, open-label study. Healthy adults were dosed with doravirine at 100 mg for 5 days once daily (QD) (period 1). Following a 7-day washout, efavirenz was administered at 600 mg QD for 14 days (period 2). Subsequently, doravirine was administered at 100 mg QD for 14 days (period 3). Blood samples were collected for pharmacokinetic analyses. Twenty healthy subjects were enrolled, and 17 completed the study. One day after efavirenz cessation, the doravirine area under the concentration-time curve from predosing to 24 h postdosing (AUC0–24), maximum observed plasma concentration (C max), and observed plasma concentration at 24 h postdosing (C 24) were reduced by 62%, 35%, and 85%, respectively, compared with the values with no efavirenz pretreatment. These decreases recovered to 32%, 14%, and 50% for AUC0–24, C max, and C 24, respectively, by day 14 after efavirenz cessation. The doravirine C 24 reached projected therapeutic trough concentrations, based on in vitro efficacy, on day 2 following efavirenz cessation. Geometric mean efavirenz concentrations were 3,180 ng/ml on day 1 and 95.7 ng/ml on day 15, and efavirenz was present at therapeutic concentrations (>1,000 ng/ml) until day 4. Though doravirine exposure was transiently decreased following efavirenz treatment cessation, dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed population.

scholarly journals Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects

2014 ◽  
Vol 58 (11) ◽  
pp. 6696-6700 ◽  
Author(s):  
Ivy Song ◽  
Julie Borland ◽  
Shuguang Chen ◽  
Amanda Peppercorn ◽  
Toshihiro Wajima ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Subjects ◽  
Integrase Inhibitor ◽  
Pharmacokinetic Analysis ◽  
Hiv Integrase ◽  
Open Label ◽  
Naive Patient ◽  
Time Curve ◽  
Once Daily ◽  
Treatment Comparison

ABSTRACTDolutegravir (DTG) is an HIV integrase inhibitor (INI) with demonstrated activity in INI-naive and INI-resistant patients. The objective of this open-label, 2-period, single-sequence study was to evaluate the effect of fosamprenavir-ritonavir (FPV-RTV) on the steady-state plasma pharmacokinetics of DTG. Twelve healthy subjects received 50 mg DTG once daily for 5 days (period 1), followed by 10 days of 50 mg DTG once daily in combination with 700/100 mg FPV-RTV every 12 h (period 2). All doses were administered in the fasting state. Serial pharmacokinetic samples for DTG and amprenavir and safety assessments were obtained throughout the study. Noncompartmental pharmacokinetic analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated for within-subject treatment comparison. Fosamprenavir-ritonavir decreased the DTG area under the concentration-time curve, maximum concentration in plasma, and concentration in plasma at the end of the dosing interval by 35%, 24%, and 49%, respectively. Both DTG and DTG with FPV-RTV were well tolerated; no subject withdrew because of adverse events. The most frequently reported drug-related adverse events were rash, abnormal dreams, and nasopharyngitis. The modest decrease in DTG exposure when it was coadministered with FPV-RTV is not considered clinically significant, and DTG dose adjustment is not required with coadministration of FPV-RTV in INI-naive patient populations on the basis of established “no-effect” boundaries of DTG. In the INI-resistant population, as a cautionary measure, alternative combinations that do not include FPV-RTV should be considered. (This study has been registered atClinicalTrials.govunder identifier NCT01209065.)

scholarly journals Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects

2015 ◽  
Vol 59 (7) ◽  
pp. 3816-3822 ◽  
Author(s):  
Li Zhu ◽  
Matthew Hruska ◽  
Carey Hwang ◽  
Vaishali Shah ◽  
Michael Furlong ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Systemic Exposure ◽  
Open Label ◽  
Time Curve ◽  
Once Daily ◽  
Viral Attachment ◽  
Cyp3a4 Substrate ◽  
Cyp3a4 Inhibitors ◽  
To Receive ◽  
Hiv 1

ABSTRACTBMS-663068 is a prodrug of BMS-626529, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+T cells. This open-label, multiple-dose, four-sequence, crossover study addressed potential two-way drug-drug interactions following coadministration of BMS-663068 (BMS-626529 is a CYP3A4 substrate), atazanavir (ATV), and ritonavir (RTV) (ATV and RTV are CYP3A4 inhibitors). Thirty-six healthy subjects were randomized 1:1:1:1 to receive one of four treatment sequences with three consecutive treatments: BMS-663068 at 600 mg twice daily (BID), BMS-663068 at 600 mg BID plus RTV at 100 mg once daily (QD), ATV at 300 mg QD plus RTV at 100 mg QD (RTV-boosted ATV [ATV/r]), or BMS-663068 at 600 mg BID plus ATV at 300 mg QD plus RTV at 100 mg QD. Compared with the results obtained by administration of BMS-663068 alone, coadministration of BMS-663068 with ATV/r increased the BMS-626529 maximum concentration in plasma (Cmax) and the area under the concentration-time curve in one dosing interval (AUCtau) by 68% and 54%, respectively. Similarly, coadministration of BMS-663068 with RTV increased the BMS-626529Cmaxand AUCtauby 53% and 45%, respectively. Compared with the results obtained by administration of ATV/r alone, ATV and RTV systemic exposures remained similar following coadministration of BMS-663068 with ATV/r. BMS-663068 was generally well tolerated, and there were no adverse events (AEs) leading to discontinuation, serious AEs, or deaths. Moderate increases in BMS-626529 systemic exposure were observed following coadministration of BMS-663068 with ATV/r or RTV. However, the addition of ATV to BMS-663068 plus RTV did not further increase BMS-626529 systemic exposure. ATV and RTV exposures remained similar following coadministration of BMS-663068 with either ATV/r or RTV. BMS-663068 was generally well tolerated alone or in combination with either RTV or ATV/r.

scholarly journals Fosamprenavir plus Ritonavir Increases Plasma Ketoconazole and Ritonavir Exposure, while Amprenavir Exposure Remains Unchanged

2007 ◽  
Vol 51 (8) ◽  
pp. 2982-2984 ◽  
Author(s):  
Mary B. Wire ◽  
Charles H. Ballow ◽  
Julie Borland ◽  
Mark J. Shelton ◽  
Yu Lou ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
Open Label ◽  
Time Curve ◽  
Once Daily ◽  
Open Label Study ◽  
Label Study ◽  
Concentration Time

ABSTRACT Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.

scholarly journals Effect of Tipranavir-Ritonavir on Pharmacokinetics of Raltegravir

2009 ◽  
Vol 53 (7) ◽  
pp. 2752-2755 ◽  
Author(s):  
William D. Hanley ◽  
Larissa A. Wenning ◽  
Allison Moreau ◽  
James T. Kost ◽  
Eric Mangin ◽  
...  
Keyword(s):  
Geometric Mean ◽  
Study Drug ◽  
Integrase Inhibitor ◽  
Phase Iii ◽  
Open Label ◽  
Time Curve ◽  
Period 2 ◽  
Adverse Experiences ◽  
Immunodeficiency Virus

ABSTRACT Raltegravir (RAL) is a novel and potent human immunodeficiency virus type 1 integrase inhibitor that is predominantly metabolized via glucuronidation. The protease inhibitor combination tipranavir (TPV) at 500 mg and ritonavir (RTV) at 200 mg (TPV-RTV) has inhibitory and inductive effects on metabolic enzymes, which includes the potential to induce glucuronosyltransferase. Because RAL may be coadministered with TPV-RTV, there is the potential for the induction of RAL metabolism. Consequently, we assessed the effect of TPV-RTV on the pharmacokinetics of RAL and the safety and tolerability of this combination. Eighteen healthy adults were enrolled in this open-label study. The participants received RAL at 400 mg twice daily for 4 days (period 1) and TPV-RTV twice daily for 7 days (period 2), followed immediately by 400 mg RAL with TPV-RTV twice daily for 4 days (period 3). Under steady-state conditions, the RAL concentration at 12 h (C 12) was decreased when RAL was administered with TPV-RTV (geometric mean ratio [GMR], 0.45; 90% confidence interval [CI] 0.31, 0.66; P = 0.0021); however, the area under the concentration-time curve from time zero to 12 h (GMR, 0.76; 90% CI, 0.49, 1.19; P = 0.2997) and the maximum concentration in serum (GMR, 0.82; 90% CI, 0.46, 1.46; P = 0.5506) were not substantially affected. There were no serious adverse experiences or discontinuations due to study drug-related adverse experiences, and RAL coadministered with TPV-RTV was generally well tolerated. Although the RAL C 12 was decreased with TPV-RTV in this study, favorable efficacy data collected in phase III studies substantiate that TPV-RTV may be coadministered with RAL without dose adjustment.

scholarly journals Minimal Effects of Ritonavir and Efavirenz on the Pharmacokinetics of Raltegravir

2008 ◽  
Vol 52 (12) ◽  
pp. 4338-4343 ◽  
Author(s):  
Marian Iwamoto ◽  
Larissa A. Wenning ◽  
Amelia S. Petry ◽  
Martine Laethem ◽  
Marina De Smet ◽  
...  
Keyword(s):  
Maximum Concentration ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Strand Transfer ◽  
Time Curve ◽  
Period 2 ◽  
Immunodeficiency Virus ◽  
Transfer Inhibitor ◽  
Hiv 1

ABSTRACT Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration = 31 nM in 50% human serum). The possible effects of ritonavir and efavirenz on raltegravir pharmacokinetics were separately examined. Two clinical studies of healthy subjects were conducted: for ritonavir plus raltegravir, period 1, 400 mg raltegravir; period 2, 100 mg ritonavir every 12 h for 16 days with 400 mg raltegravir on day 14; for efavirenz plus raltegravir, period 1, 400 mg raltegravir; period 2, 600 mg efavirenz once daily for 14 days with 400 mg raltegravir on day 12. In the presence of ritonavir, raltegravir pharmacokinetics were weakly affected: the plasma concentration at 12 h (C 12 h) geometric mean ratio (GMR) (90% confidence interval [CI]) was 0.99 (0.70, 1.40), area under the concentration-time curve from zero to infinity (AUC0 - ∞) was 0.84 (0.70, 1.01), and maximum concentration of drug in serum (C max) was 0.76 (0.55, 1.04). In the presence of efavirenz, raltegravir pharmacokinetics were moderately to weakly reduced: C 12 h GMR (90% CI) was 0.79 (0.49, 1.28); AUC0- ∞ was 0.64 (0.52, 0.80); and C max was 0.64 (0.41, 0.98). There were no substantial differences in the time to maximum concentration of drug in plasma or the half-life. Plasma concentrations of raltegravir were not substantially affected by ritonavir. Though plasma concentrations of raltegravir were moderately to weakly reduced by efavirenz, the degree of this reduction was not clinically meaningful. No dose adjustment is required for raltegravir with coadministration with ritonavir or efavirenz.

scholarly journals Atogepant and sumatriptan: no clinically relevant drug–drug interactions in a randomized, open-label, crossover trial

2021 ◽  
Author(s):  
Ramesh Boinpally ◽  
Abhijeet Jakate ◽  
Matthew Butler ◽  
Antonia Periclou
Keyword(s):  
Plasma Concentration ◽  
Crossover Trial ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Geometric Mean ◽  
Open Label ◽  
Time Curve ◽  
Concentration Time ◽  
Pharmacokinetic Interactions ◽  
Randomized Crossover Study

Aim: To evaluate pharmacokinetic interactions of atogepant with sumatriptan, an open-label, randomized, crossover study was conducted. Patients & methods: Thirty healthy adults received atogepant 60 mg, sumatriptan 100 mg, or coadministered drugs. Primary end point was geometric mean ratios (GMRs) and 90% CIs of interventions for area under the plasma concentration–time curve from time 0 to t (AUC0-t) or infinity (AUC0-∞) and peak plasma concentration (Cmax). Results: Atogepant GMRs for AUC0-t and AUC0-∞ versus with sumatriptan were within 90% CI 0.80–1.25, indicating no interaction; atogepant Cmax was reduced by 22% (GMR: 0.78; 90% CI: 0.69–0.89) with sumatriptan. Sumatriptan GMRs for AUC0-t, AUC0-∞ and Cmax versus with atogepant were within 90% CI 0.80–1.25. Conclusion: Atogepant with sumatriptan had no clinically relevant pharmacokinetic interactions.

scholarly journals Effects Of Korean Red Ginseng On The Pharmacokinetics And Pharmacodynamics Of Metformin In Healthy Subjects

2020 ◽  
Vol 6 (6) ◽  
pp. 1-8
Author(s):  
Young-Ran Yoon ◽  
◽  
Sook Jin Seong ◽  
Keyword(s):  
Blood Glucose ◽  
Healthy Subjects ◽  
Geometric Mean ◽  
Clinical Importance ◽  
Systemic Exposure ◽  
Red Ginseng ◽  
Open Label ◽  
Korean Red Ginseng ◽  
Time Curve ◽  
Multiple Doses

Characterizing potential interactions between red ginseng, an herb with desirable health effects, and metformin, a commonly used drug for the treatment of type 2 diabetes mellitus, is of high clinical importance. In this study, we evaluate the effects of Korean red ginseng on the pharmacokinetic and pharmacodynamic properties of metformin in healthy subjects. The study was conducted in an open-label, two-period and single-sequence design. A total of 11 subjects received multiple doses of metformin in the first study period followed by multiple doses of metformin and red ginseng in the second study period. The Geometric Mean Ratio (GMR) (90% Confidence Interval (CI)) between the groups for area under the plasma drug concentration-time curve within a dosing interval (tau) at steady state (AUCtau,ss) of metformin was out of the range of bioequivalence, indicating that the systemic exposure of metformin when combined with red ginseng was reduced compared with administration of metformin alone. However, the pharmacodynamic analysis showed that the GMR (90% CI) between the groups for area under the blood glucose values–time curve from time zero to the time of the last measurable value (AUClast) and maximum blood glucose value (Gmax) were within the range of bioequivalence. We concluded that the observed reduction in the systemic exposure of metformin when administered with red ginseng is clinically insignificant. This study demonstrated that Korean red ginseng did not have clinically significant pharmacokinetic or pharmacodynamic herb–drug interactions with metformin in healthy subjects.

scholarly journals An Open-Label Study of the Impact of Hepatic Impairment on the Pharmacokinetics and Safety of Single Oral and Intravenous Doses of Omadacycline

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Steven J. Kovacs ◽  
Lillian Ting ◽  
Jens Praestgaard ◽  
Gangadhar Sunkara ◽  
Haiying Sun ◽  
...  
Keyword(s):  
Hepatic Impairment ◽  
Healthy Subjects ◽  
Geometric Mean ◽  
The United States ◽  
Moderate Hepatic Impairment ◽  
Severe Hepatic Impairment ◽  
Open Label ◽  
Time Curve ◽  
The Impact ◽  
Mild Hepatic Impairment

ABSTRACT Omadacycline is a once-daily oral or intravenous (i.v.) aminomethylcycline antibiotic approved in the United States for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults. Omadacycline pharmacokinetics were characterized in 18 patients with hepatic impairment and 12 matched healthy subjects. Patients with hepatic impairment received i.v. omadacycline at 100 mg (mild hepatic impairment) or 50 mg (moderate and severe hepatic impairment) and oral omadacycline at 300 mg (mild hepatic impairment) or 150 mg (moderate hepatic impairment); oral omadacycline was not evaluated in those with severe hepatic impairment. Safety monitoring included the collection of adverse events (AEs), performance of laboratory tests, determination of vital signs, and performance of electrocardiograms. Omadacycline exposures were similar in patients with hepatic impairment and healthy subjects following i.v. or oral administration, with the geometric mean ratios for the area under the concentration-time curve and the maximum drug concentration ranging from 0.79 to 1.42. Omadacycline was safe and well tolerated. Overall, 13/30 (43.3%) participants experienced an AE; those occurring in more than 1 participant included headache (13.3%), nausea (6.7%), infusion-site pain (6.7%), contusion (6.7%), and dizziness (6.7%), with no differences based on the degree of hepatic impairment or the route of administration. Asymptomatic increases in heart rate were observed; none was considered an AE. These findings suggest that no omadacycline dose adjustment is warranted in patients with hepatic impairment.

scholarly journals Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Sauzanne Khalilieh ◽  
Ka Lai Yee ◽  
Rosa I. Sanchez ◽  
Ilias Triantafyllou ◽  
Li Fan ◽  
...  
Keyword(s):  
Single Dose ◽  
Drug Interactions ◽  
Geometric Mean ◽  
Cancer Resistance ◽  
Serious Adverse Events ◽  
Fixed Sequence ◽  
Once Daily ◽  
Relevant Effect ◽  
Hiv 1

ABSTRACT Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, hypercholesterolemia is often treated with statins, including the commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug interactions with cytochrome P450 3A4 (CYP3A4) inhibitors. Increased exposure due to CYP3A4 inhibition may lead to serious adverse events (AEs), including rhabdomyolysis. Furthermore, atorvastatin is a substrate for breast cancer resistance protein (BCRP), of which doravirine may be a weak inhibitor; this may increase atorvastatin exposure. The potential of doravirine to affect atorvastatin pharmacokinetics was investigated in a two-period, fixed-sequence study in healthy individuals. In period 1, a single dose of atorvastatin at 20 mg was administered followed by a 72-h washout. In period 2, doravirine at 100 mg was administered once daily for 8 days, with a single dose of atorvastatin at 20 mg concomitantly being administered on day 5. Sixteen subjects were enrolled, and 14 completed the trial; 2 discontinued due to AEs unrelated to the treatment. The atorvastatin area under the curve from time zero to infinity was similar with and without doravirine (geometric mean ratio [GMR] for doravirine-atorvastatin/atorvastatin, 0.98; 90% confidence interval [CI], 0.90 to 1.06), while the maximum concentration decreased by 33% (GMR for doravirine-atorvastatin/atorvastatin, 0.67; 90% CI, 0.52 to 0.85). These changes were deemed not to be clinically meaningful. Both of the study drugs were generally well tolerated. Doravirine had no clinically relevant effect on atorvastatin pharmacokinetics in healthy subjects, providing support for the coadministration of doravirine and atorvastatin.

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