Efavirenz does not meaningfully affect the single dose pharmacokinetics of 1200 mg raltegravir

Raltegravir is a human immunodeficiency virus (HIV)‐1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once daily regimen (QD) at a dose of 1200 mg (2 x 600 mg) is under development and offers a new treatment option for HIV‐1 infected treatment‐naive subjects. Since raltegravir is eliminated mainly by metabolism via an UDP‐glucuronosyltransferase (UGT) 1 A1‐mediated glucuronidation pathway, co‐administration of UGT1A1 inducers may alter plasma levels of raltegravir. Efavirenz, an UGT1A1 inducer, was used to assess the impact of altered UGT activity on a 1200 mg QD dose of raltegravir. An open label, randomized, 2‐period fixed‐sequence Phase 1 study was performed in adult healthy male and female subjects (non‐childbearing potential) ≥ 19 and ≤55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤32.0 kg/m². Subjects (n = 21) received a single oral dose of 1200 mg raltegravir at bedtime on an empty stomach on Day 1 in Period 1. After a washout period of at least 7 days, subjects received oral doses of 600 mg efavirenz QD at bedtime for 14 consecutive days in Period 2. Subjects received a single oral dose of 1200 mg raltegravir co‐administered with 600 mg efavirenz on Day 12 of Period 2. Pharmacokinetic (PK) samples were collected for 72 hours following raltegravir dosing and analyzed using a validated bioanalytical method to quantify raltegravir plasma concentrations. PK parameters were estimated using non‐compartmental analysis. Administration of single 1200 mg oral doses of raltegravir alone and co‐administered with multiple oral doses of efavirenz were generally well tolerated in healthy subjects. Co‐administration with efavirenz yielded geometric mean ratios (GMRs) and their associated 90% confidence intervals (90% CIs) for raltegravir AUC_0‐∞, C_max, and C₂₄ of 0.86 (0.73, 1.01), 0.91 (0.70, 1.17), and 0.94 (0.76, 1.17), respectively. The results show that efavirenz modestly reduced the exposure of raltegravir. The reduction in raltegravir exposure is not considered clinically meaningful. Copyright © 2016 John Wiley & Sons, Ltd.     

Assessment of the pharmacokinetics of co-administered maraviroc and raltegravir

AIMS

To assess the two-way pharmacokinetic interaction between maraviroc and raltegravir.

METHODS

In this open-label, multiple-dose, fixed-sequence study, 18 healthy, human immunodeficiency virus (HIV)-seronegative subjects received the following: days 1–3 raltegravir 400 mg q12h, days 4–5 washout, days 6–11 maraviroc 300 mg q12h, and days 12–14 raltegravir 400 mg q12h + maraviroc 300 mg q12h. Serial 12-h blood samples were collected on days 3 (raltegravir), 11 (maraviroc) and 14 (raltegravir + maraviroc). Plasma samples were assayed by validated liquid chromatography tandem mass spectrometry assays. Test/reference ratios and 95% confidence intervals (CIs) were determined for pharmacokinetic parameters.

RESULTS

For maraviroc, the test/reference % ratio (95% CI) for AUC_τ was 85.8 (78.7, 93.5), for C_max was 79.5 (64.8, 97.5) and for C_min was 90.3 (84.2, 96.9). For raltegravir, the test/reference % ratio (95% CI) for AUC_τ was 63.3 (41.0, 97.6), for C_max was 66.8 (37.1, 120.0) and for C_min was 72.4 (55.1, 95.2). In all subjects, maraviroc average concentrations (AUC_τ divided by 12) were >100 ng ml⁻¹, the threshold value below which there is an increased risk of virological failure. Based on clinical experience for raltegravir, mean C_min decreases >60% are considered to be clinically relevant for short-term activity; however, in the present study mean changes were only 28% and thus not considered to be of clinical relevance.

CONCLUSIONS

Co-administration of maraviroc and raltegravir decreased systemic exposure of both drugs; however, these are not likely to be clinically relevant. Safety and efficacy studies may help in understanding the role of this combination in the treatment of HIV infection.     

A sensitive liquid chromatography coupled with mass spectrometry method for the intracellular and plasma quantification of raltegravir after solid-phase extraction

Introduction Liquid chromatography coupled with mass spectrometry for the quantification of raltegravir in human plasma and peripheral blood mononuclear cells has been developed. Methods Sample preparations were based on a fully automated solid‐phase extraction process. Mass spectrometric data were acquired in a single‐ion monitoring method. Raltegravir and quinoxaline, the internal standard, were well separated in a gradient mode over 15 min. Key findings Validation study exhibited excellent linearity, with good intra‐ and inter‐day precision and accuracy. Conclusions The assay was successfully applied to the raltegravir quantification in HIV‐infected patients.     

Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women

AIMS

Oral contraceptives such as norgestimate–ethinyl estradiol (Ortho Tri-Cyclen®) are commonly prescribed in the HIV-infected patient population. A placebo-controlled, randomized, two-period crossover study in healthy HIV-seronegative subjects was conducted to assess the effect of raltegravir on the pharmacokinetics of the estrogen and progestin components of norgestimate–ethinyl estradiol [ethinyl estradiol (EE) and norelgestromin (NGMN), an active metabolite of norgestimate (NGT)].

METHODS

In each of two periods, nineteen healthy women established on norgestimate–ethinyl estradiol contraception (21 days of active contraception; 7 days of placebo) received either 400 mg raltegravir or matching placebo twice daily on days 1–21. Pharmacokinetics were analysed on day 21 of each period.

RESULTS

The geometric mean ratio (GMR) and 90% confidence interval (CI) for the EE component of norgestimate–ethinyl estradiol when co-administrated with raltegravir relative to EE alone was 0.98 (0.93–1.04) for the area under the concentration–time curve from 0 to 24 h (AUC_{0–24 h}) and 1.06 (0.98–1.14) for the maximum concentration of drug in the plasma (C_max); the GMR (90% CI) for the NGMN component of norgestimate–ethinyl estradiol when co-administered with raltegravir relative to NGMN alone was 1.14 (1.08–1.21) for AUC_{0–24 h} and 1.29 (1.23–1.37) for C_max. There were no discontinuations due to a study drug-related adverse experience, nor any serious clinical or laboratory adverse experience.

CONCLUSIONS

Raltegravir has no clinically important effect on EE or NGMN pharmacokinetics. Co-administration of raltegravir and an oral contraceptive containing EE and NGT was generally well tolerated; no dose adjustment is required for oral contraceptives containing EE and NGT when co-administered with raltegravir.     

Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects

Aim

This study examined the effects of grapefruit juice on the new P2Y₁₂ inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein.

Methods

In a randomized crossover study, 10 healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90 mg dose of ticagrelor.

Results

Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (C_max) to 165% (95% confidence interval 147, 184%) and area under the concentration–time curve (AUC(0,∞)) to 221% of control (95% confidence interval 200, 245%). The C_max and AUC(0,34 h) (P < 0.05) but not the AUC(0,∞) of the active metabolite C12490XX were decreased significantly. Grapefruit juice had a minor effect on ticagrelor elimination half-life prolonging it from 6.7 to 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® methods, and postponed the recovery of platelet reactivity.

Conclusions

Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice–ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.     

Pharmacokinetics,food intake requirements and tolerability of once-daily combinations of nelfinavir and low-dose ritonavir in healthy volunteers

AIMS: This study was performed to evaluate the steady-state pharmacokinetics, food intake requirements and short-term tolerability of once-daily combinations of nelfinavir and low-dose ritonavir. METHODS: Twenty-seven healthy volunteers were randomized over three groups to receive a once-daily regimen of nelfinavir/ritonavir 2,000/200 mg (group 1), 2,000/400 mg (group 2) or 2,500/200 mg (group 3) with food for 14 days. Pharmacokinetic parameters for nelfinavir and its active metabolite M8 were assessed on study days 15 and 16, after administration of the regimens with a full (610 kcal) or light (271 kcal) breakfast, respectively. RESULTS: Pharmacokinetic data were evaluable for eight volunteers in group 1, eight in group 2 and four in group 3. Administration of nelfinavir/ritonavir with a full breakfast resulted in geometric mean (GM) nelfinavir AUC(24h) values of 76.8, 51.3, and 61.9 h*mg/l in group 1, 2 and 3, respectively. GM 24-h Cmin concentrations of nelfinavir were 0.76 mg l(-1), 0.43 mg l(-1) and 0.47 mg l(-1), respectively. Co-administration of ritonavir increased M8 concentrations more than nelfinavir concentrations, resulting in GM AUC(24h) and Cmin values for nelfinavir plus M8 that were higher than or comparable to reference values for the approved regimen of nelfinavir (1,250 mg BID without ritonavir). In the 2,000/200 mg group, seven out of eight subjects had a Cmin value of nelfinavir plus M8 above a threshold of 1.0 mg l-1. Administration of the combinations with a light breakfast resulted in significant decreases in the AUC(24h) and Cmin of nelfinavir and nelfinavir plus M8, compared with intake with a full breakfast. For the Cmin of nelfinavir plus M8, the GM ratio (light/full breakfast) was 0.76 (90% confidence interval 0.67-0.86, participants from all groups combined). Short-term tolerability was satisfactory, apart from a higher than expected incidence of mild rash (12%). CONCLUSIONS: Administration of nelfinavir in a once-daily regimen appears feasible. A nelfinavir/ritonavir 2,000/200 mg combination appears appropriate for further evaluation. Once-daily nelfinavir/ritonavir should be taken with a meal containing at least 600 kcal.     

Effect of a single daily dose treatment of fenofibrate on plasma lipoproteins in hyperlipoproteinaemia IIb

Summary The safety and efficacy of a single daily dose of fenofibrate (200 mg) have been evaluated in 12 Type IIB hyperlipidaemic patients in a three-month study. At the same time the pharmacokinetics was studied to check whether this new dosage schedule would give a therapeutic plasma levels of fenofibrate.At the single daily dose of 200 mg, fenofibrate was highly effective, very well tolerated, and it reached therapeutic plasma levels without accumulation.It appears that fenofibrate can usefully be employed at this dosage in hyperlipidaemia, especially since patient compliance is better when only one daily dose need be taken.     

A safety evaluation of raltegravir for the treatment of HIV

Introduction: Raltegravir (RAL) was the first commercialized agent from a new drug class with an innovative target, the integrase. Since its introduction in clinical practice RAL has become widely used for the treatment of HIV-1 infected patients. A decade after its approval, this article reviews key evidence from RAL with a special interest on safety outcomes.

Areas covered: Pharmacologic, safety and efficacy data of RAL from clinical trials and post-commercialization published reports are hereby summarized after a literature review including PubMed search, relating proceedings and abstracts from relevant international HIV conferences, assessment reports from European and United States regulatory agencies and treatment guidelines (World Health Organization, United States Department of Health and Human Services and European AIDS Clinical Society), up to October 2017. Most frequent search terms were ‘raltegravir’, ‘safety’, ‘adverse events’, ‘efficacy’ and ‘integrase-inhibitors’.

Expert opinion: Despite the arrival of new integrase strand transfer inhibitors (INSTIs) with advantages in terms of dosing convenience (elvitegravir, ELV) and higher genetic barrier (dolutegravir, DTG), RAL has stood the test of time and its overall favourable safety profile, without significant appearance of unexpected adverse events, vouch for its relevance in the antiretroviral armamentarium.     

A conventional LC-MS method developed for the determination of plasma raltegravir concentrations

Raltegravir belongs to a new class of antiretrovirals acting for a human immunodeficiency virus (HIV)-1 integrase inhibition. Clinical trials of this drug have demonstrated potent antiviral activity in both therapy na?ve and experienced patients. Thus, raltegravir has become an important component of combination treatment regimens used to treat patients with multidrug-resistant HIV-1. The quantification of raltegravir in human plasma is important to support clinical studies and determine pharmacokinetic parameters of raltegravir in HIV-1 infected patients. Recently, the LC-MS/MS superfine system was developed to determine plasma concentration of raltegravir; however, the system needs to be delicately set and the equipment is very expensive. Therefore, we developed a conventional LC-MS method to overcome these difficulties. Subsequently the method was validated by estimating the precision and accuracy for inter- and intraday analysis in the concentration range of 0.010-7.680 microg/ml. The calibration curve was linear in this range. Average accuracy ranged from 97.2 to 103.4%. Relative standard deviations of both inter- and intraday assays were less than 10.4%. Recovery of raltegravir was more than 80.6%. This novel LC-MS method is accurate and precise enough to determine raltegravir levels in human plasma samples.     

Itraconazole moderately increases serum concentrations of oxybutynin but does not affect those of the active metabolite

Objective: Oxybutynin has low oral bioavailability due to an extensive presystemic metabolism. It has been suggested that the biotransformation of oxybutynin is dependent on CYP3A. Because itraconazole, a widely used mycotic, is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between oxybutynin and itraconazole. Methods: In this double-blind, randomized, two-phase cross-over study, ten healthy volunteers received either 200 mg itraconazole or placebo for 4 days. On day 4, each volunteer ingested a single dose of 5 mg oxybutynin. Serum concentrations of oxybutynin, its active metabolite N-desethyloxybutynin, and itraconazole were monitored over 24 h. Results: Itraconazole significantly increased both the area under the serum drug concentration-time curve (AUC_0–t) and the peak concentration of oxybutynin twofold. The AUC_0–t and the peak concentration of N-desethyloxybutynin were not significantly affected by itraconazole. Itraconazole did not change the peak time or the elimination half-life of either oxybutynin or N-desethyloxybutynin. The occurrence of adverse events after oxybutynin administration was not increased by itraconazole. Conclusions: Itraconazole moderately increases serum concentrations of oxybutynin, probably by inhibiting the CYP3A-mediated metabolism. However, the concentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributable to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 inhibiting drugs has only minor clinical significance. Received: 29 October 1996 / Accepted in revised form: 13 February 1997     

Single dose and steady-state pharmacokinetics of 4 mg and 8 mg oral salbutamol controlled-release in patients with bronchial asthma

Summary Fifteen patients with asthma were given salbutamol controlled-release (SCR) 4 mg or 8 mg twice daily for seven days, in a randomised double-blind cross-over design. Plasma salbutamol levels were measured after the first and fifteenth doses for a 12 h period following drug ingestion.At steady-state the geometric mean values for C_max were 8.2 ng/ml for 4 mg, and 16.1 ng/ml for 8 mg. Median t_max values were 300 and 240 min respectively. The geometric mean AUC (0–12) were 4507 ng·min·ml^–1 and 8980 ng·min/ml. Peak to trough fluctuation ratios were 0.577 and 0.572.There were no significant differences between 4 mg or 8 mg formulations, for any of the parameters measured, after appropriate corrections for dose. The concentration-time profiles at steady-state showed little fluctuation in plasma salbutamol levels over the twelve hour dosing interval. These results show that 4 mg and 8 mg formulations of SCR provide smooth plasma profiles at steady-state with a twice daily dosing regime.Part of this paper has been presented in abstract form to the British Thoracic Society, Newcastle, July 1988     

健康人连续口服不同剂量胺碘酮的血药浓度的临床研究

目的　比较中国健康受试者连续口服胺碘酮不同剂量后,各种药代动力学参数的特点。方法　16名健康男性受试者随机分为两组,第一组 (A组 )连续口服胺碘酮 800mg·d-1;第二组(B组 )连续口服胺碘酮 200mg·d-1。采用HPLC法测定血浆中的胺碘酮及其代谢物去乙基胺碘酮浓度。结果　A、B两组的达峰浓度Cmax分别为 ( 1 17±0 38 )和(0 84±0 33)mg·L-1,达峰时间Tmax分别为(4 0±2 0)和(5 1±1 4)h,终末消除半衰期 (T1 /2 )分别为 ( 410 5±137 1)和(345 9±237 0)h,组间比较均无差异;A组、B组起作用浓度分别为 ( 0 93±0 28 )和 ( 0 57±0 25 ) mg·L-1,差异有统计学意义;A组、B组发生药物反应的时间及累积剂量基本一致;发生药物反应的浓度A组 ( 0 71 ~1 34)mg·L-1,B组 ( 0 29 ~1 11 )mg·L-1。结论　在一定时间内,随口服胺碘酮剂量增加,血药浓度相应增加,提示在临床用药中如在开始用药时通过给与较大剂量的负荷量,可能获得更快的起效作用。     

The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects

AIMS: Our aim was to investigate the effect of the CYP2C8 inhibitor trimethoprim on the pharmacokinetics and pharmacodynamics of the antidiabetic drug repaglinide, and to examine the influence of the former on the metabolism of the latter in vitro. METHODS: In a randomized, double-blind, crossover study with two phases, nine healthy volunteers took 160 mg trimethoprim or placebo orally twice daily for 3 days. On day 3, 1 h after the last dose of trimethoprim or placebo, they ingested a single 0.25 mg dose of repaglinide. Plasma repaglinide and blood glucose concentrations were measured for up to 7 h post-dose. In addition, the effect of trimethoprim on the metabolism of repaglinide by human liver microsomes was investigated. RESULTS: Trimethoprim raised the AUC(0, infinity ) and C(max) of repaglinide by 61% (range, 30-117%; P= 0.0008) and 41% (P = 0.005), respectively, and prolonged the t((1/2)) of repaglinide from 0.9 to 1.1 h (P = 0.001). Trimethoprim had no significant effect on the pharmacokinetics of its aromatic amine metabolite (M1), but decreased the M1 : repaglinide AUC(0, infinity ) ratio by 38% (P = 0.0005). No effect of trimethoprim on the blood glucose-lowering effect of repaglinide was detectable. In vitro, trimethoprim inhibited the metabolism of (220 nm) repaglinide in a concentration-dependent manner. CONCLUSIONS: Trimethoprim raised the plasma concentrations of repaglinide probably by inhibiting its CYP2C8-mediated biotransformation. Although the interaction did not significantly enhance the effect of repaglinide on blood glucose concentration at the drug doses used, the possibility of an increased risk of hypoglycaemia should be considered during concomitant use of trimethoprim and repaglinide in patients with diabetes.     

Concentrations in plasma, urinary excretion and bactericidal activity of levofloxacin (500 mg) versus ciprofloxacin (500 mg) in healthy volunteers receiving a single oral dose

In a randomised crossover study, 14 volunteers received a single oral dose of 500 mg levofloxacin or 500 mg ciprofloxacin in order to assess plasma concentrations by high-pressure liquid chromatography (up to 24 h), urinary excretion and urinary bactericidal titres (UBTs) at intervals up to 120 h. The median maximum concentration of levofloxacin in plasma was 6.1 mg/L and that of ciprofloxacin was 2.3 mg/L. The median cumulative level of renal excretion of the administered dose of the parent drug was 81.2% for levofloxacin and 36.2% for ciprofloxacin. UBTs were determined for a reference strain and nine clinical uropathogens. The median UBTs of both quinolones measured within the first 12 h were between 0 and 1:≥1024, correlating with the minimum inhibitory concentrations (MICs) of the strains. For Gram-negative strains, the UBTs of both quinolones were comparable despite the lower MICs of ciprofloxacin. During further time courses, however, the UBTs of levofloxacin were significantly higher than those of ciprofloxacin. For Gram-positive strains, for which the MICs of levofloxacin were equal to or lower than those of ciprofloxacin, the UBTs of levofloxacin were already significantly higher from the beginning. It can be concluded that overall the doses of the two tested fluoroquinolones may be considered equivalent with regard to treatment of complicated urinary tract infections, although the recommended dosing is twice daily for ciprofloxacin and once daily for levofloxacin.     

A pharmacokinetic model-independent approach for estimating dose required to give desired steady-state trough concentrations of drug in plasma

A maintenance dose designed to give a desired minimum concentration of drug in plasma at steady-state can be determined in a model-independent manner assuming that concentration-time data needed for the calculation are obtained after absorption and distribution are complete. Using a few concentration-time points obtained after the first dose, numerical values of and Z, a parameter consisting of different pharmacokinetic parameters for different models, can be obtained. An administration interval () can be chosen based on . Using the values of , Z, and , a maintenance dose is calculated. This approach will allow calculation of a maintenance dose when drug is present in plasma at the time the first monitored dose is given.     

Pharmacokinetics and dose proportionality of extended-release metformin following administration of 1000, 1500, 2000 and 2500 mg in healthy volunteers

The pharmacokinetics and dose-exposure relationship of an extended-release formulation of metformin (ER-metformin) was investigated in a randomized, single-dose, four-period crossover study in 24 healthy male volunteers. During each study period, subjects received a randomly assigned dose containing 1000, 1500, 2000 or 2500 mg metformin. Blood samples were drawn 0-72 h after dosing for pharmacokinetic and dose-proportionality assessment. Although several pairwise comparisons between dose groups were significant (p<0.05) with respect to dose-normalized C(max), AUC(0-72 h), and AUC( infinity ), the magnitude of the difference across the dose range was <20% for AUC(0-72 h) and AUC( infinity ), and was < or = 30% for C(max). The results indicate a consistent and predictable increase in metformin exposure with an extended-release formulation of metformin over 1000 to 2500 mg.