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

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

SUBMITTER: Bukkems VE

PROVIDER: S-EPMC7894397 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Bukkems Vera E VE Post Teun M TM Colbers Angela P AP Burger David M DM Svensson Elin M EM

CPT: pharmacometrics & systems pharmacology 20210125 2

Once-daily two 600 mg tablets (1200 mg q.d.) raltegravir offers an easier treatment option compared to the twice-daily regimen of one 400 mg tablet. No pharmacokinetic, efficacy, or safety data of the 1200 mg q.d. regimen have been reported in pregnant women to date as it is challenging to collect these clinical data. This study aimed to develop a population pharmacokinetic (PopPK) model to predict the pharmacokinetic profile of raltegravir 1200 mg q.d. in pregnant women and to discuss the expec ...[more]

PMID: 33369217

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Project description:Because studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were randomized to receive 400 mg once daily (QD) or 800 mg QD for 2 weeks, followed by the other dosing for 2 weeks. Intensive pharmacokinetic analyses were performed, and HIV RNA was monitored. Two patients were excluded from the 400-mg QD analysis due to inevaluable pharmacokinetic data. The mean patient weight was 58 kg. Mean pharmacokinetic values were as follows: for raltegravir given at 400 mg BID, the area under the concentration-time curve from 0 to 12 h (AUC????) was 15.6 mg/liter-h and the minimum plasma drug concentration (C(trough)) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC???? was 33.6 mg/liter-h and the C(trough) was 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC???? was 18.6 mg/liter-h and the C(trough) was 0.08 mg/liter. The HIV RNA load was <50 copies/ml at each dose level. Compared to the adjusted AUC???? for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC???? and those on raltegravir at 400 mg QD had a similar AUC????. More patients had a C(trough) of <0.021 mg/liter on raltegravir at 400 mg QD (9/17 patients) than on raltegravir at 800 mg QD (1/19 patients) or 400 mg BID (0/19 patients). Seventeen patients used raltegravir at 400 mg QD for a median of 35 weeks; two had confirmed HIV RNA loads between 50 and 200 copies/ml, and both had low C(trough) values. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a low C(trough) and with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed.

Project description:The aim of this study was to evaluate the plasma and intracellular pharmacokinetics of raltegravir in HIV-infected patients receiving once-daily raltegravir. Five HIV-infected patients on stable therapy with lopinavir-ritonavir monotherapy whose HIV-1 RNA load was <50 copies/ml were included in this open-label, pilot study. Raltegravir was added to the antiretroviral regimen at a dose of 800 mg once daily from days 0 to 10. On day 10, a full pharmacokinetic profile was obtained for each participant. Raltegravir concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were determined by high-performance liquid chromatography with a fluorescence detector and by liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively. The values of the raltegravir pharmacokinetic parameters in plasma and PBMCs were calculated by noncompartmental analysis. Raltegravir was well tolerated, and all participants completed the study. No differences in the times to the maximum concentration of raltegravir in plasma or the raltegravir half-lives were observed between plasma and PBMCs. The geometric mean raltegravir maximum concentration, the concentration at the end of the dosing interval, and the area under the concentration-time curve during the dose interval in plasma versus PBMCs were 2,640 ng/ml (range, 887 to 10,605 ng/ml) versus 199 ng/ml (range, 82 to 857 ng/ml) (geometric mean ratio [GMR], 13.30; 95% confidence interval [CI], 3.11 to 56.89; P = 0.003); 89 ng/ml (range, 51 to 200 ng/ml) versus 7 ng/ml (range, 2 to 15 ng/ml) (GMR, 13.21; 95% CI, 3.94 to 44.26; P = 0.001); and 12,200 ng·h/ml (range, 5,152 to 30,130 ng·h/ml) versus 909 ng·h/ml (range, 499 to 2,189 ng·h/ml) (GMR, 13.43; 95% CI, 5.13 to 35.16; P < 0.001), respectively. Raltegravir does not accumulate in PBMCs, with intracellular concentrations being about 1/10 of the concentrations in plasma. Despite once-daily dosing, mean raltegravir concentrations at the end of the dosing interval in plasma and PBMCs exceeded the reported protein-binding-adjusted 95% inhibitory concentration (IC(95)) and IC(50) for wild-type viral strains, respectively.

Project description:Administering raltegravir once daily would make adherence to antiretroviral treatment easier, especially if the concomitant drugs are also administered once daily. We report our experience on the use of raltegravir, both once- and twice-daily.Retrospective review of HIV-infected patients on treatment with raltegravir 800?mg once or 400?mg twice a day plus 2 analogs. Patients were classified as group A (subjects switched to raltegravir due to adverse events on a previous regimen or drug-drug interactions) and group B (subjects who restarted antiretroviral treatment after a previous drop-out). The primary clinical endpoint was the percentage of subjects with virological suppression after 96 weeks. Treatment's effectiveness (noncomplete/missing equals failure) was also evaluated. Pharmacokinetic study was performed in unselected patients. Plasma raltegravir concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry.A total of 133 patients were included in the study (74 and 59 on raltegravir once- and twice-daily). There were only 4 virological failures in the entire cohort during the follow-up. Thus, the Kaplan-Meier estimation of efficacy by on-treatment analysis was 96.3% (CI95, 92.8-99.8) at week 96, independently of the dosing regimen and of the raltegravir concentrations. Similar exposures to raltegravir based on AUC0-?, but higher Cmax and significantly lower Ctrough were observed when raltegravir was given once daily compared with 400?mg twice daily. In fact, 14 out of 56 Ctrough concentrations (25%) from patients taking raltegravir once daily were below the IC95 of wild-type HIV-1 clinical isolates while only 2 samples from patients receiving 400?mg twice a day were below this value, although no relationship between Ctrough and efficacy was found. The main limitations of the study are that the raltegravir dosing regimen was not randomized and more than 50% of the patients were virologically suppressed at baseline.Regimens comprising raltegravir 800?mg once daily plus 2 nucleos(t)ide reverse transcriptase inhibitors can be an efficacious and safe option, particularly in virologically suppressed patients and those with a viral load <100,000?copies/mL.

Project description:BackgroundThe efficacy, safety and tolerability of lumiracoxib, a novel selective cyclooxygenase-2 (COX-2) inhibitor, has been demonstrated in previous studies of patients with osteoarthritis (OA). As it is important to establish the long-term safety and efficacy of treatments for a chronic disease such as OA, the present study compared the effects of lumiracoxib at doses of 100 mg once daily (o.d.) and 100 mg twice daily (b.i.d.) with those of celecoxib 200 mg o.d. on retention on treatment over 1 year.MethodsIn this 52-week, multicentre, randomised, double-blind, parallel-group study, male and female patients (aged at least 40 years) with symptomatic primary OA of the hip, knee, hand or spine were randomised (1:2:1) to lumiracoxib 100 mg o.d. (n = 755), lumiracoxib 100 mg b.i.d. (n = 1,519) or celecoxib 200 mg o.d. (n = 758). The primary objective of the study was to demonstrate non-inferiority of lumiracoxib at either dose compared with celecoxib 200 mg o.d. with respect to the 1-year retention on treatment rate. Secondary outcome variables included OA pain in the target joint, patient's and physician's global assessments of disease activity, Short Arthritis assessment Scale (SAS) total score, rescue medication use, and safety and tolerability.ResultsRetention rates at 1 year were similar for the lumiracoxib 100 mg o.d., lumiracoxib 100 mg b.i.d. and celecoxib 200 mg o.d. groups (46.9% vs 47.5% vs 45.3%, respectively). It was demonstrated that retention on treatment with lumiracoxib at either dose was non-inferior to celecoxib 200 mg o.d. Similarly, Kaplan-Meier curves for the probability of premature discontinuation from the study for any reason were similar across the treatment groups. All three treatments generally yielded comparable results for the secondary efficacy variables and all treatments were well tolerated.ConclusionLong-term treatment with lumiracoxib 100 mg o.d., the recommended dose for OA, was as effective and well tolerated as celecoxib 200 mg o.d. in patients with OA.Trial registrationclinicaltrials.gov NCT00145301.

Dataset Information

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

Publications

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

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