Journal of Clinical Pharmacology最新文献

The objective of the study was to determine the impact of food and different meal types on the pharmacokinetics of rilpivirine, a nonnucleoside reverse transcriptase inhibitor. In this open-label, randomized, crossover study, healthy volunteers received a single, oral 75 mg dose of rilpivirine either with a normal-fat breakfast (reference), under fasting conditions, with a high-fat breakfast, or with a protein-rich nutritional drink. Pharmacokinetic parameters were determined by non-compartmental methods and analyzed using a linear mixed-effects model. Safety was assessed throughout. The least-squares mean ratio for area under the plasma concentration-time curve to last timepoint was 0.57 (90% confidence interval [CI]: 0.46-0.72) under fasting conditions compared to dosing with a normal-fat breakfast. With a high-fat breakfast or only a protein-rich nutritional drink, the corresponding values were 0.92 (90% CI: 0.80-1.07) and 0.50 (90% CI: 0.41-0.61), respectively, compared to dosing with a normal-fat breakfast. Under all conditions, rilpivirine was generally safe and well tolerated. Administration of rilpivirine under fasting conditions or with only a protein-rich nutritional drink substantially lowered the oral bioavailability when compared to administration with a normal-fat breakfast. Rilpivirine bioavailability was similar when administered with a high-fat or normal-fat breakfast. Rilpivirine should always be taken with a meal to ensure adequate bioavailability.

Cyclosporine A (CsA) shows significant inter-individual variability in its pharmacokinetics, which may be due to polymorphisms in ABCB-1 genes coding for P-glycoprotein. The aim of this study was to explore the role of genetic polymorphisms of ABCB-1 in affecting the CsA blood concentrations in renal transplanted patients over the first 3 months after transplantation. Renal transplanted patients receiving CsA (n = 40) were genotyped for ABCB -1 C3435T (I1145I) and G1199A (S400N) polymorphisms. CsA blood concentrations were measured on Day 7, 30, and 90 after transplantation. G1199A variant showed higher CsA blood concentrations in stable patients, that was significant for trough levels (198 vs. 136 ng/mL on Day 7, P = .004, 196 vs. 125 ng/mL on Day 30, P = .007, 194 vs. 121 ng/mL on Day 90, P = .005 for stable vs. unstable groups). Polymorphisms of ABCB-1 have only a minor effect on CsA blood concentrations. The functional G1199A polymorphism can affect the drug levels more than non-functional C3435T. This polymorphism might be of a potential prognostic value in renal transplanted patients.

Radix Puerariae has been traditionally used for the treatment of diarrhea, acute dysentery, deafness and cardiovascular diseases. Yege (Gegen or Radix Puerariae lobatae), the dried root of Pueraria lobata (Wild.) Ohwi, has been widely used in China and, to a lesser extent, in Japan, Korea, and the United States. Although they have been classified into different categories in Chinese Pharmacopoeia, Yege is often used interchangeably in practice with Fenge (Radix Puerariae thomsonii), which is the dried root of Pueraria thomsonii Benth. Among various commercially available products of Radix Puerariae, injection of puerarin, the major isoflavone from Radix Puerariae, has been most widely used as a vasodilator for the treatment of angina and myocardial infarction. Considering the extensive clinical usage and recent alert of fatal herb-drug interaction of Radix Puerariae, the current review is proposed to cover its traditional applications, pharmacological activities, pharmacokinetics, clinical efficacy, and potential herb-drug interactions aiming to fill in the information gaps of this herb for frontline practitioners. Although various small, poorly designed clinical trials have demonstrated the safety, efficacy, and significant clinical benefits of Radix Puerariae, prospective randomized controlled clinical trials are needed to further establish its effective and safe use.

Voclosporin (VCS) is a novel calcineurin (CN) inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the single ascending dose pharmacokinetics (PK) and pharmacodynamics (PD, CN activity) of VCS and the effect of food. VCS was administered orally in single doses of 0.25 through 4.5 mg/kg in 62 subjects in the single ascending dose study and as a single oral 1.5 mg/kg dose to 18 subjects after fasting, consumption of a low-fat and high-fat meal. Non-compartmental PK, PD, and PKPD correlation were evaluated. Following single oral doses, systemic exposure increased in a linear manner and demonstrated 1:1 dose-proportional, first-order linear PK above 1.5 mg/kg. VCS inhibited CN activity in a dose-related fashion with maximal inhibition peaking at 3.0 mg/kg. PKPD correlation indicated an EC50 of 78.3 ± 6.8 ng/mL. Administration of VCS with a low-fat and high-fat meal decreased C(max) by 29% and 53%, respectively, and AUC(inf) by 15% and 25%, respectively. Following ascending single doses of VCS, exposure increased in a linear fashion. A food effect on exposure was demonstrated, with a more pronounced effect following a high-fat meal. VCS concentrations were also found to correlate with CN activity.

The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which statistical differences existed between each pair of specific pathways. A number of DDIs were simulated (Simcyp Pediatric v12) for virtual compounds to highlight effects of age on fractional elimination and consequent magnitude of DDI. For a theoretical drug metabolized 50% by each of CYP2D6 and CYP3A4 pathways at birth, co-administration of ketoconazole (3 mg/kg) resulted in a 1.65-fold difference between inhibited versus uninhibited AUC compared to 2.4-fold in 1 year olds and 3.2-fold in adults. Conversely, neonates could be more sensitive to DDI than adults in certain scenarios. Thus, extrapolation from adult data may not be applicable across all pediatric age groups. The use of pediatric physiologically based pharmacokinetic (p-PBPK) models may offer an interim solution to uncovering potential periods of vulnerability to DDI where there are no existing clinical data derived from children.

Based on an analysis of the Magdeburg Dronedarone Registry data we sought to determine which patients could benefit from dronedarone therapy regarding rhythm control. The study included 191 patients (85 women) aged 63 ± 10 years with a history of paroxysmal or persistent AF and a follow-up of 14 ± 5 months. The total AF recurrence rate was 67% and lone AF was significantly more often associated with AF recurrences than non-lone AF (84% vs. 62%, P = .01). Arterial hypertension, treated coronary artery disease, and diabetes mellitus were not significantly related to AF recurrences (64%, 67%, 58% resp. P = .3). Response rate to dronedarone in patients with slightly increased left atrial size was significantly greater than in patients with normal or markedly increased left atrial size (47%, 16%, 27% resp., P = .001). The rate of adverse effects was 32% in the study sample, and was significantly lower in patients with lone AF as compared to those with non-lone AF (11% vs. 37%, P = .002). The body mass index was a predictor neither of response rate nor adverse effects. The results suggest that dronedarone is more effective in patients with non-lone AF and slightly increased left atrial size.

Recent interest in NK1 receptor antagonists has focused on a potential role in the treatment of drug addiction and substance abuse. In the present study, the potential for interactions between the NK1 receptor antagonist aprepitant and alcohol, given as an infusion at a target level of 0.65 g/L, was evaluated. Amitriptyline was included as positive control to provide an impression of the profile of central nervous system (CNS) effects. In a double-blind, randomized, placebo- and amitriptyline-controlled study, the pharmacokinetics and CNS effects of aprepitant and alcohol were investigated in 16 healthy volunteers. Cognitive and psychomotor function tests included the visual verbal learning test (VVLT), Bond and Lader visual analogue scales (VAS), digit symbol substitution test (DSST), visual pattern recognition, binary choice reaction time, critical flicker fusion (CFF), body sway, finger tapping, and adaptive tracking. Alcohol impaired finger tapping and body sway. Amitriptyline impaired DSST performance, VAS alertness, CFF, body sway, finger tapping, and adaptive tracking. No impairments were found after administration of aprepitant. Co-administration of aprepitant with alcohol was generally well tolerated and did not cause significant additive CNS effects, compared with alcohol alone. Therefore, our study found no indications for clinically relevant interactions between aprepitant and alcohol.

Trastuzumab is a key component of treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in both the early and metastatic settings. It is administered intravenously, with between 17 and 52 infusions in standard regimens over 1 year. Intravenous administration of trastuzumab requires substantial time commitments for patients and health care professionals and can result in patient discomfort. A subcutaneous formulation of trastuzumab, containing recombinant human hyaluronidase to overcome subcutaneous absorption barriers, would reduce the administration duration and remove the need to establish intravenous access, thus improving the overall convenience of trastuzumab administration. This open-label, 2-part, phase I/Ib study (NCT00800436) was undertaken in healthy male volunteers and female patients with HER2-positive early breast cancer to identify the dose of subcutaneous trastuzumab that resulted in exposure comparable with the approved intravenous trastuzumab dose. A subcutaneous trastuzumab dose of 8 mg/kg was found to result in exposure comparable with the intravenous trastuzumab dose of 6 mg/kg. The subcutaneous formulation was well tolerated, with a trend toward fewer adverse events versus intravenous administration; most adverse events were mild in intensity. These results support an ongoing phase III efficacy and safety study comparing a fixed subcutaneous trastuzumab dose with intravenous trastuzumab administration.

Relationships between tocilizumab exposure and response were evaluated using data from 4 phase III studies. Increased tocilizumab exposure was associated with improvements in Disease Activity Score using 28 joints (DAS28) and American College of Rheumatology (ACR) criteria and with a decrease in inflammation markers. A population pharmacokinetic/pharmacodynamic (PKPD) model was developed to describe data from 2 studies. An indirect-response model with a sigmoid E_max (maximal drug effect) inhibitory drug effect on DAS28 "production" rate adequately described the relationship between tocilizumab concentration and DAS28. Mean minimum serum tocilizumab concentration at steady state was greater than the EC₅₀ (concentration at which 50% of E_max on DAS28 is reached) with the 8-mg/kg dose but not with the 4-mg/kgdose. Simulations within a large rheumatoid arthritis (RA) population showed that DAS remission rates were 38% for 8 mg/kg and 24% for 4 mg/kg. Tocilizumab was more potent in RA patients with higher baseline interleukin-6 levels, but this effect was not clinically significant. Other covariates (eg, presence of neutralizing antitocilizumab antibodies) did not demonstrate a clinically meaningful effect on tocilizumab DAS28 dose-response relationships. These data support clinical observations that tocilizumab 8 mg/kg is more effective than 4 mg/kg in reducing disease activity.

The internationalization of clinical and regulatory guidelines and disease treatment and the globalization of the pharmaceutical industry have led drug development strategies in Japan to shift from bridging studies to multinational trials. However, the current standard for adequate dose-finding processes may sometimes complicate the timely participation of Japan in these multinational trials. The objective of this study is to investigate different factors that might influence dosage selection in Japan. Approved drug dosages in Japan and the United States during the period 2003-2008 were compared and assessed across different therapeutic areas and approval timings. Factors such as company type and daily dosage indication were demonstrated to have a statistically significant relationship with different dosages in Japan and the United States. Anticancer, antiviral, and enzyme drugs showed similar dosages in the 2 regions, whereas neurological drugs were observed to undergo more careful dosage-finding processes, resulting in the approval of generally lower doses in Japan. A broader analysis is needed for detailed assessment. The findings in this study serve as an initial review to identify important factors that should be considered before planning global drug development.