Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel

ABSTRACT

Objective: Clopidogrel is an oral thienopyridine antiplatelet agent indicated for the treatment of atherothrombotic events in patients with acute coronary syndrome (ACS). Prasugrel, a novel oral thienopyridine, is under investigation for the reduction of atherothrombotic events in patients with ACS undergoing percutaneous coronary intervention. Prasugrel's solubility decreases with increasing pH, suggesting that concomitantly-administered medications that increase gastric pH may lower the rate and/or extent of prasugrel absorption. This study evaluated the influence of ranitidine coadministration on the pharmacokinetics and pharmacodynamics of the respective active metabolite of prasugrel and clopidogrel.

Research design and methods: In this open-label, two-period, two-treatment, crossover study, 47 healthy male subjects were randomized to one of two study arms, receiving either prasugrel (60-mg loading dose [LD], 10-mg maintenance dose [MD] for 7?days; n?=?23) or clopidogrel (600-mg LD, 75-mg MD for 7?days; n?=?24). In one treatment period, subjects received prasugrel or clopidogrel alone, and in the alternate period received the same thienopyridine with ranitidine (150?mg twice daily, starting 1?day before the LD). Pharmacokinetic parameter estimates (AUC_{0?t last}, C_max, and t_max) and inhibition of platelet aggregation (IPA) by light transmission aggregometry were assessed at multiple time points after the LD and final MD.

Results: Ranitidine had no clinically significant effect on the area under the plasma-concentration-time curve (AUC) and did not affect the time to C_max (t_max) for active metabolites of either prasugrel or clopidogrel. It reduced the geometric mean maximum concentrations of active metabolite (C_max) after a prasugrel and clopidogrel LD by 14% and 10%, respectively, but these differences were not statistically significant. When coadministered with a 60-mg prasugrel LD, ranitidine did not affect the time to, or magnitude of, peak IPA, but did result in a modest reduction at 0.5?h from 67.4 to 55.1% (p?<?0.001). Ranitidine did not affect prasugrel IPA during MD. For clopidogrel, IPA was not affected by ranitidine. Prasugrel and clopidogrel were both well-tolerated, with/without ranitidine.

Conclusions: Results from this study suggest that there is no significant drug–drug interaction between oral ranitidine therapy and concomitantly-administered prasugrel or clopidogrel.     

松果菊苷药动/药效研究进展与思考

本文综述了近年来松果菊苷（ECH）在抗衰老、提高记忆力与神经保护、抗肿瘤、保护肝脏及免疫调节等方面的药理作用研究进展,探讨了其可能的作用机制。此外,还对ECH的吸收和代谢等药代动力学最新研究进展进行总结,并将其药效学特征与药代动力学行为进行联系与比较,指出了ECH药效学和药代动力学之间存在的表面矛盾,并就如何解释这些矛盾进行了探讨。在此基础上,提出天然来源的创新药物通常具有系统前广泛代谢的特点,发挥整体药效作用的可能是其活性代谢产物;应针对中药I类新药的这些特点,加强系统前代谢转化研究;并制订科学合理的临床前药物代谢动力学技术指导原则,用以指导具有类似特点的中药I类新药的研究。     

The effect of fluvastatin on the pharmacokinetics and pharmacodynamics of ezetimibe

ABSTRACT

Objective: The objective of this study was to evaluate the pharmacodynamic effects and safety of the co-administration of ezetimibe and fluvastatin in healthy hypercholesterolemic subjects at clinically-relevant doses and to evaluate the potential for a pharmacokinetic drug interaction between ezetimibe and fluvastatin.

Methods: In a single-center, evaluator-blind, placebo-controlled, multiple-dose, parallel-group study 32 healthy subjects with hypercholesterolemia were randomized to 4 treatments administered once daily for 14 days: ezetimibe 10?mg plus ezetimibe placebo, fluvastatin 20?mg plus ezetimibe placebo, fluvastatin 20?mg plus ezetimibe 10?mg, and ezetimibe placebo. Blood samples were collected to measure serum lipids and to determine steady-state pharmacokinetics.

Results: Ezetimibe 10?mg significantly (?p ≤ 0.01) decreased total-cholesterol and low-density lipoprotein cholesterol (LDL‐C) concentrations compared to placebo at Day 14. Fluvastatin 20?mg also caused a significant (?p = 0.01) reduction in total-cholesterol and a decrease in LDL‐C at Day 14 compared to placebo, however, the decrease in LDL‐C did not reach statistical significance (?p = 0.08). The coadministration of ezetimibe 10?mg and fluvastatin 20?mg caused significantly (?p ≤ 0.01) greater mean percent reductions in LDL‐C and total-cholesterol than fluvastatin 20?mg alone or placebo at Day 14. Fluvastatin had no clinically significant effect on the pharmacokinetics of ezetimibe. On average, ezetimibe appeared to decrease the rate and extent of fluvastatin bioavailability.

Conclusion: Coadministration of ezetimibe and fluvastatin was safe and well tolerated and caused significant incremental reductions in LDL‐C and total cholesterol compared to fluvastatin administered alone. The pharmacokinetics of ezetimibe were not affected by coadministration with fluvastatin. The apparent decrease in fluvastatin exposure on administration with ezetimibe was likely to be due to the parallel study design and two pharmacokinetic outliers and is considered of no clinical significance.     

Intrapulmonary pharmacokinetics and pharmacodynamics of meropenem

The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered meropenem in healthy volunteers. Four doses of 0.5 g, 1.0 g or 2.0 g meropenem were administered intravenously to 20, 20 and 8 healthy adult subjects, respectively. Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed following administration of the last dose. Blood was obtained for drug assay prior to drug administration and at the time of BAL. Meropenem was measured in plasma, BAL fluid and alveolar cells (ACs) using a combined high pressure liquid chromatographic–mass spectrometric technique. Plasma, epithelial lining fluid (ELF) and AC pharmacokinetics were derived using non-compartmental methods. C_max/MIC₉₀ (where C_max is the maximum plasma concentration and MIC₉₀ is the minimum inhibitory concentration required to inhibit 90% of the pathogen), AUC/MIC₉₀ (where AUC is the area under the curve for the mean concentration–time data), intrapulmonary drug exposure ratios and percent time above MIC₉₀ during the dosing interval (%T > MIC₉₀) were calculated for common respiratory pathogens with MIC₉₀ values of 0.12–4 μg/mL. In the 0.5 g dose group, the C_max (mean ± S.D.), AUC_0–8 h and half-life for plasma were, respectively, 25.8 ± 5.8 μg/mL, 28.57 μg h/mL and 0.77 h; for ELF the values were 5.3 ± 2.5 μg/mL, 12.27 μg h/mL and 1.51 h; and for ACs the values were 1.0 ± 0.5 μg/mL, 4.30 μg h/mL and 2.61 h. In the 1.0 g dose group, the C_max, AUC_0–8 h and half-life for plasma were, respectively, 53.5 ± 19.7 μg/mL, 55.49 μg h/mL and 1.31 h; for ELF the values were 7.7 ± 3.1 μg/mL, 15.34 μg h/mL and 0.95 h; and for ACs the values were 5.0 ± 3.4 μg/mL, 14.07 μg h/mL and 2.17 h. In the 2.0 g dose group, the C_max, AUC_0–8 h and half-life for plasma were, respectively 131.7 ± 18.2 μg/mL, 156.7 μg h/mL and 0.89 h. The time above MIC in plasma ranged between 28% and 78% for the 0.5 g dose and between 45% and 100% for the 1.0 g and 2.0 g doses. In ELF, the time above MIC ranged from 18% to 100% for the 0.5 g dose and from 25% to 88% for the 1.0 g dose. In ACs, the time above MIC ranged from 0% to 100% for the 0.5 g dose and from 24% to 100% for the 1.0 g dose. Time above MIC in ELF and ACs for the 2.0 g dose was not calculated because of sample degradation. The prolonged T > MIC₉₀ and high intrapulmonary drug concentrations following every 8 h administration of 0.5–2.0 g doses of meropenem are favourable for the treatment of common respiratory pathogens.     

Effects of ezetimibe on the pharmacodynamics and pharmacokinetics of lovastatin

SUMMARY

Background: Ezetimibe is a cholesterol absorption inhibitor which decreases low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. This study investigated the potential for pharmacodynamic and/or pharmacokinetic interactions between ezetimibe and lovastatin.

Methods: In a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study, 48 healthy men with hypercholesterolemia (screening LDL-C ≥ 130?mg/dL) who were stabilized and maintained on a National Cholesterol Education Program (NCEP) Step I diet were randomized to one of the following six oral treatments once daily for 14?days: lovastatin 20?mg; lovastatin 20?mg plus ezetimibe 5, 10, or 20?mg; lovastatin 40?mg plus ezetimibe 10?mg; or placebo.

Results: Reported adverse events were generally mild, nonspecific, and similar among treatments. There were no significant changes in safety laboratory test results, including those for enzymes indicative of muscle or liver injury. Co-administration of ezetimibe and lovastatin did not increase the plasma concentrations of lovastatin or β-hydroxylovastatin. In this parallel comparison study there was an apparent decrease in lovastatin exposure, however, the reduction in lovastatin or β-hydroxylovastatin concentrations was not related to the ezetimibe dose and is not considered to be clinically important. Ezetimibe 5, 10, or 20?mg combined with lovastatin 20?mg caused a significantly (?p < 0.01) greater reduction in LDL-C than lovastatin 20?mg alone, with no apparent effect on HDL-C or triglycerides. LDL-C was reduced by 51.0% with ezetimibe 10?mg plus lovastatin 20?mg, 56.0% with ezetimibe 10?mg plus lovastatin 40?mg, 33.2% with lovastatin alone, and 17.3% with placebo.

Conclusions: The co-administration of ezetimibe and lovastatin was well tolerated and resulted in a significantly greater percentage reduction in serum LDL-C concentrations than with lovastatin alone, with an average incremental reduction of 16–18%. Ezetimibe 10?mg appears to be the optimal dose when co-administered with lovastatin 20?mg once daily. Further incremental reductions in LDL-C from the co-administration of ezetimibe and lovastatin are expected only when the dose of lovastatin is increased. The co-administration of ezetimibe and lovastatin has the potential to produce clinically significant reductions in LDL-C compared to either drug alone, with favorable safety and tolerability.     

Modelling the pharmacokinetics and pharmacodynamics of trimazosin

The pharmacokinetics and pharmacodynamics of trimazosin are described following both intravenous and oral administration to 6 normotensive, male volunteers. The IV and oral drug and metabolite (1-hydroxytrimazosin) concentration data are fitted simultaneously to the same pharmacokinetic model. The pharmacodynamic response, change in systolic blood pressure following 5 min in the erect posture, is described using several possible models. The most efficient is one which attributes the response to both the parent drug and its principal metabolite. The response following oral administration is also consistent with this model. It appears that the reduction in blood pressure following administration of trimazosin at steady state may be governed by the concentration of metabolite.     

头孢美唑的药动药效学与临床

头孢美唑（ＣＭＺ）为一种半合成头霉素类抗生素，本品在日本和欧美已较广泛应用，国内从１９８８年起进行了临床观察及验证。结果表明ＣＭＺ有抗菌谱广，耐酶稳定，体内分布好，不良反应低等特点。具有良好的临床应用价值。本文概述了近年国内外有关ＣＭＺ的药动药效学及临床应用研究情况，以其供临床应用本品时参考。     

A study of the effects of zimeldine on the pharmacokinetics and pharmacodynamics of temazepam in healthy volunteers

In this double-blind two-period crossover study, ten healthy volunteers received either 200 mg zimeldine each morning for 5 days, or placebo on the same schedule. On day 5 they received 20 mg temazepam 2 h after zimeldine or placebo. A battery of psychometric tests and subjective measurements was carried out on days 4 and 5. Blood samples were collected on day 5 for pharmacokinetic analysis of temazepam.All the measures of psychomotor performance showed the effects of temazepam, as did two of the subjective measures, the alert/drowsy and steady/dizzy visual analogue scales. No effect of zimeldine alone on performance or subjective state was seen. Zimeldine showed no discernible interaction with the effects of temazepam as assessed by subjective reports, by psychomotor tests, or by pharmacokinetic analysis.     

The effect of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin in humans

Objective: The interaction of multiple oral doses of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin was investigated in six healthy male volunteers. Methods: The subjects were given individually adjusted doses of warfarin to achieve therapeutic levels of prothrombin activity. The established daily maintenance oral dose of warfarin was kept stable throughout the trial and, on study days 8–14, each volunteer received a 800-mg daily dose of cimetidine. The degree of anticoagulant response produced by warfarin was quantified by the determination of both the prothrombin time and factor-VII clotting activity. Results: Cimetidine co-administration had no significant effect on the pharmacokinetics of the more potent S-warfarin but significantly increased by 28% (P < 0.05) mean R-warfarin trough plasma concentrations and decreased by 23% (P < 0.05) mean R-warfarin apparent clearance. Both prothrombin time and factor-VII clotting activity displayed considerable inter-subject variability and were not significantly affected by concurrent cimetidine treatment. The reduction of apparent clearance of R-warfarin by cimetidine was found to be the effect of inhibition of the formation of warfarin metabolites as determined by apparent formation clearance values (±SD) of R-6-hydroxywarfarin (31.1 ± 7.4 ml/h baseline; 18.5 ± 4.5 ml/h at end of cimetidine treatment; P < 0.01), and R-7-hydroxywarfarin (6.9 ± 1.3 ml/h baseline; 4.3 ± 1.1 ml/h at end of cimetidine treatment; P < 0.01). Conclusion: Cimetidine stereoselectively affects the steady-state pharmacokinetics of warfarin by inhibiting the disposition of the less potent R-warfarin in humans. However, this interaction is likely to be of minimal clinical significance in most patients. Received: 11 December 1998 / Accepted in revised form: 17 March 1999     

Assessment of preclinical pharmacokinetics and acute toxicity of pioglitazone and telmisartan combination

The prevalence of hypertension is very common amongst the diabetic patients and is reported as the major cause of mortality in diabetes. Pioglitazone reported to have an ability to alter the blood cholesterol level and cardioprotective efficiency along with its antidiabetic activity. Telmisartan, through activation of PPAR-γ receptor exerts insulin sensitizing property in addition to its primary cardioprotective efficiency. Theoretically, a combination of pioglitazone and telmisartan may be beneficial to effectively control the high blood glucose level and management of coexisting cardiovascular complication in diabetes. The aim of this research was to experimentally evaluate the pharmacokinetic interaction of pioglitazone and telmisartan when are coadministered in rat. Pioglitazone and telmisartan were administered orally as a single dose individually and in combination to the rats. The plasma samples of the pharmacokinetic study were analyzed using a validated LCMS method. The acute toxicity of the combination with a high dose in rats was also evaluated as a part of the determination of its safety profile. There was no significant change in pharmacokinetic parameters were resulted due to the coadministration of pioglitazone and telmisartan in rat. Absence of major toxicological effect supports the in vivosafety of the combination.     

Effect of nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

Objective  Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro, nebicapone has showed an inhibitory effect upon CYP2C9, which is responsible for the metabolism of S-warfarin. The objective of this study was to investigate the effect of nebicapone on warfarin pharmacokinetics and pharmacodynamics in healthy subjects. Methods  Single-centre, open-label, randomised, two-period crossover study in 16 healthy volunteers. In one period, subjects received nebicapone 200 mg thrice daily for 9 days and a racemic warfarin 25-mg single dose concomitantly with the nebicapone morning dose on day 4 (test). In the other period, subjects received a racemic warfarin 25-mg single dose alone (reference). The treatment periods were separated by a washout of 14 days. Results  For R-warfarin, mean ± SD C_max was 1,619 ± 284 ng/mL for test and 1,649 ± 357 ng/mL for reference, while AUC_0-t was 92,796 ± 18,976 ng·h/mL (test) and 73,597 ± 11,363 ng·h/mL (reference). The R-warfarin test-to-reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) were 0.973 (0.878–1.077) for C_max and 1.247 (1.170–1.327) for AUC_0-t . For S-warfarin, mean ± SD C_max was 1,644 ± 331 ng/mL for test and 1,739 ± 392 ng/mL for reference, while AUC_0-t was 66,627 ± 41,199 ng·h/mL (test) and 70,178 ± 42,560 ng·h/mL (reference). The S-warfarin test-to-reference GMR and 90%CI were 0.932 (0.845–1.028) for C_max and 0.914 (0.875–0.954) for AUC_0-t . No differences were found for the pharmacodynamic parameter (INR). Conclusion  Nebicapone showed no significant effect on S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R-warfarin metabolism was found but is unlikely to be of clinical relevance.     

Diazepam: Prediction of pharmacodynamics from pharmacokinetics

The use of a pharmacokinetic/pharmacodynamic/receptor binding model to predict the onset and duration of the parmacological effect of diazepam was explored. The analysis examined the effects of diazepam (0.28 mg/kg) on the wheel-tracking and digit-symbol substitution performance of young healthy adults. Both free-plasma drug concentration and relative amount of diazepam bound to the benzodiazepine receptor were calculated and compared to the behavioral measures across time. Performance was more significant correlated with relative receptor occupancy (RRO) than with unbound plasma-drug levels. For both tasks hysteresis plots indicated greater similarity between time profiles of performance and RRO than between those of performance and blood concentration alone. These results provide support for the inclusion of both receptor binding kinetics and plasma pharmacokenetics as the bases for the prediction of the parmacologic activity of diazepam.     

Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin

Objective To examine the effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. Aprepitant is a neurokinin-1 (NK₁)-receptor antagonist developed as an antiemetic for chemotherapy-induced nausea and vomiting.Methods This was a double-blind, placebo-controlled, randomized, two-period, parallel-group study. During period 1, warfarin was individually titrated to a stable prothrombin time (expressed as international normalized ratio, INR) from 1.3 to 1.8. Subsequently, the daily warfarin dose remained fixed for 10–12 days. During period 2, the warfarin dose was continued for 8 days, and on days 1–3 administered concomitantly with aprepitant (125 mg on day 1, and 80 mg on days 2 and 3) or placebo. At baseline (day –1 of period 2) and on day 3, warfarin pharmacokinetics was investigated. INR was monitored daily. During period 2, warfarin trough concentrations were determined daily.Results The study was completed by 22 healthy volunteers (20 men, 2 women). On day 3, steady-state pharmacokinetics of warfarin enantiomers after aprepitant did not change, as assessed by warfarin AUC_0-24h and C_max. However, compared with placebo, trough S(–) warfarin concentrations decreased on days 5–8 (maximum decrease 34% on day 8, P<0.01). The INR decreased after aprepitant with a mean maximum decrease on day 8 of 11% versus placebo (P=0.011).Conclusion These data are consistent with a significant induction of CYP2C9 metabolism of S(–) warfarin by aprepitant. Subsequently, in patients on chronic warfarin therapy, the clotting status should be monitored closely during the 2-week period, particularly at 7–10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle.     

布比卡因白蛋白微球的制备及药理学研究

目的制备盐酸布比卡因人血清白蛋白微球(Bupi-HSA-MS),并对其体内药动学、药效学及生物相容性进行评价。方法采用高压电场法制备布比卡因人血清白蛋白微球,采用改良的反相高效液相色谱法测定体内布比卡因血药浓度,以家兔为实验对象,以针刺疼痛反应圈直径大小评价其麻醉效果。结果药动学实验结果表明,注射剂组血药浓度达峰值时间短,浓度高,药物驻留时间短。微球组峰值浓度显著低于注射剂组并长时间维持低浓度。微球组MRT较对照组明显延长(P<0.01)。微球组皮下给药最大麻醉圈直径明显小于注射剂对照组(P<0.01),而微球组局麻持续时间较对照组明显延长(P<0.01)。结论高压电场法是一种简单、易行的白蛋白微球制备新方法。Bupi-HSA-MS兔皮下给药,药物扩散少,局部麻醉作用持续时间长,是一种安全长效的局部麻醉止痛新方法。     

Effects of water deprivation on the pharmacokinetics and pharmacodynamics of bumetanide in rats

The effects of temporary water deprivation for 48 h on the pharmacokinetics and pharmacodynamics of bumetanide were examined after intravenous (i.v.) administration of bumetanide, 8 mg kg^?1 to control and water deprived rats (n = 7). The values of AUC, t_1/2 and MRT increased 79.0, 417, and 633 per cent, respectively, and CL and CL_NR decreased 44.0 and 41.2 per cent, respectively, in water deprived rats. They were all significantly different. The decreased CL_NR in water deprived rats could be due to decreased nonrenal metabolism of bumetanide; it could be supported that the amounts of glucuronide conjugate of bumetanide (52.5 vs 12.9 μg), desbutylbumetanide (170 vs 113 μg) and its glucuronide conjugation (191 vs 125 μg), and sum of the three metabolites (414 vs 229 μg), which are expressed in terms of bumetanide excreted in 24 h urine, decreased significantly in water deprived rats. The 8-h urine outputs per 100 g body weight (4.32 vs 1.34 ml) also reduced significantly in water deprived rats, and it might be due to significantly reduced amounts of bumetanide excreted in 8 h urine (90.9 vs 25.7 μg) and/or reduced kidney function in water deprived rats. The kidney function based on CL_lot (9.87 vs 2.14 ml min^?1 kg^?1) reduced significantly in water deprived rats. The 8-h urinary excretions of sodium (0.430 vs 0.0818 mmol), potassium (0.567 vs 0.270 mmol), and chloride (0.549 vs 0.0624 mmol) per 100 g body weight also reduced significantly in water deprived rats.     

姜黄素纳米乳的制备和药动学及药效学研究

目的 探究姜黄素纳米乳在大鼠体内的药动学特性和对大鼠高脂血症的药效作用。方法 建立大鼠血浆中姜黄素的高效液相色谱-质谱联用（HPLC-MS）含量测定方法,考察纳米乳的体内药动学过程。建立SD大鼠高脂血症动物模型,初步考察姜黄素纳米乳对高脂饮食诱导的大鼠高脂血症的药效作用。结果 体内药动学研究结果表明,以姜黄素原料药为参比制剂,姜黄素纳米乳的相对生物利用度为313.47%;以市售片剂为参比制剂,姜黄素纳米乳的相对生物利用度为279.52%。纳米乳组的Cmax为原料药组的201.48%,为片剂组的193.02%,且比原料药组及片剂组具有更高的MRT值（为原料药组的183.52%,是片剂组的154.21%）。药效学研究结果表明姜黄素纳米乳口服给药系统能显著降低模型大鼠的血清总胆固醇（TC）、低密度脂蛋白（LDLc）,缓解高脂饮食给模型大鼠造成的肝脏脂质沉积及肝损伤。结论 姜黄素纳米乳口服给药系统能够有效改善姜黄素的生物利用度,具有良好的降血脂作用,并能够控制高脂血症大鼠体重增长和改善由脂质代谢紊乱造成的肝脏系数变化。     

Assessment of the pharmacokinetics of co-administered metformin and lobeglitazone,a thiazolidinedione antihyperglycemic agent,in healthy subjects

Abstract

Objective:

Lobeglitazone as a thiazolidinedione antihyperglycemic agent activates peroxisome proliferator-activated receptor (PPAR) γ and may be suitable as monotherapy or in combination with other antihyperglycemic agents. The primary objective of this study was to investigate potential pharmacokinetic interactions between lobeglitazone and metformin in healthy Korean subjects.     

Safety,pharmacokinetics and pharmacodynamics of atacicept in healthy volunteers

Objective Atacicept, a recombinant fusion protein, blocks the activity of BLyS (a B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) and may be a potential treatment for B-cell-mediated diseases. This study assesses the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of atacicept. Methods In this Phase I study, healthy male volunteers received a single subcutaneous dose of atacicept (2.1, 70, 210 or 630 mg) or placebo and were monitored over 7 weeks for injection-site pain, local tolerability, vital signs, echocardiography, haematology, coagulation, blood chemistry, serum virology, urinalysis and PK/PD markers [lymphocyte cell counts, BLyS–atacicept complex, immunoglobulin G (IgG), IgM]. Results Atacicept was well tolerated at all doses (n = 23). There were no clinically significant changes in vital signs or laboratory parameters during the study. Treatment-emergent adverse events (AEs) were mainly mild or moderate in severity, and all were transient, resolving without any clinical sequelae. There was no evidence of any relationship between atacicept dose and the incidence of AEs. Local tolerability was good. Serum atacicept peaked 16 h after dosing, and the area under the concentration-time curve increased in an approximately dose-related manner. The 70-, 210- and 630-mg doses of atacicept demonstrated a dose-dependent biological effect on IgM levels, which was apparent up to 210 days post-dose. There were no treatment-related effects on IgG levels or lymphocyte subpopulations. Conclusions These results showed that single subcutaneous doses of atacicept were well tolerated in healthy volunteers, demonstrated non-linear PK and were biologically active, according to IgM levels.     

基因多态性对氨氯地平药代、药效的影响

氨氯地平是二氢吡啶钙离子通道阻滞剂,临床上用于各种高血压和心绞痛的治疗,在体内经CYP3A5代谢而消除,其药代动力学不同于其他的二氢吡啶钙离子通道阻滞剂。由于CYP3A存在基因多态性而导致氨氯地平药代动力学的个体差异。为此,笔者查阅国内外相关文献对氨氯地平的临床应用与CYP3A5基因多态性对其药代动力学及药效学的影响进行综述,为临床参考基因多态性特征来确立氨氯地平正确合理的给药方案提供依据。