国产环孢素胶囊在健康人体的生物等效性研究

目的:评价国产与进口环孢素胶囊的生物等效性。方法:采用随机交叉自身对照试验设计,19名健康男性志愿受试者先后单剂口服国产与进口环孢素胶囊300 mg,用HPLC法测定全血中环孢素A的浓度,以DAS1.0生物等效性评价程序处理经时血药浓度数据。结果:国产与进口环孢素A的AUC0-t分别为9045.86±1119.30μg·h·L-1和8532.17±1140.83μg·h·L-1;AUC0-∞分别为10249.03±1607.78μg·h·L-1和9373.26±1742.89μg·h·L-1;Cmax分别为1692.69±330.06μg.L-1和1645.88±292.37μg.L-1;Tmax分别为1.45±0.50h和1.33±0.43h;T1/2分别为22.20±7.81h和19.43±4.19h。以进口制剂为参比,国产环孢素胶囊的相对生物利用度为108.42±20.20%。等效性检验显示两制剂生物等效。结论:国产与进口环孢素胶囊在健康人体具有生物等效性。     

麻敏维C缓释胶囊人体生物等效性研究

目的评价麻敏维C缓释胶囊（每粒含盐酸伪麻黄碱90mg和马来酸氯苯那敏4mg）在人体的生物等效性。方法于2006年6月采用随机交叉自身前后对照试验设计,26例受试者分别单次和多次空腹口服麻敏维C缓释胶囊（试验制剂）和复方盐酸伪麻黄碱缓释胶囊（参比制剂）,与不同时间点取血样,采用液-质联用（HPLC/MS）法测定人血浆中盐酸伪麻黄碱和马来酸氯苯那敏的浓度,以DAS软件计算药物代谢动力学参数,并进行生物等效性评价。结果单次给药后,两组分的主要药物代谢动力学参数无统计学意义（P〉0.05）。试验制剂中马来酸氯苯那敏和盐酸伪麻黄碱生物利用度分别为104.31%和109.19%。多次给药后,两组分的主要药物代谢动力学参数无统计学意义（P〉0.05）。试验制剂的马来酸氯苯那敏和盐酸伪麻黄碱的生物利用度分别为103.58%和99.37%。结论麻敏维C缓释胶囊和复方盐酸伪麻黄碱缓释胶囊具有生物等效性。     

盐酸多奈哌齐口腔崩解片人体药物代谢动力学和生物等效性试验

目的采用高效液相色谱-质谱联用法研究盐酸多奈哌齐口腔崩解片的人体药物代谢动力学,并评价其生物等效性。方法 2009年9月-11月对22例健康男性受试志愿者单次交叉口服盐酸多奈哌齐口腔崩解片(试验制剂)和盐酸多奈哌齐普通片(参比制剂),测定给药后不同时间点血浆中多奈哌齐经时血药浓度,采用DAS 2.0软件进行药物代谢动力学参数计算和生物等效性评价。结果受试者单次口服试验制剂与参比制剂后,达峰时间分别为(2.95±1.16)、(3.19±0.98)h,峰浓度分别为(9.98±2.93)、(9.13±2.05)ng/mL,药时曲线下面积(0-t)分别为(470.76±142.64)、(446.57±137.30)ng/mL.h;药时曲线下面积(0-∞)分别为(517.74±169.79)、(489.47±162.13)ng/mL.h。试验制剂与参比制剂的生物等效性结果为104.7%,其90%置信区间为(98.4%,111.4%)。结论盐酸多奈哌齐口腔崩解片与普通片生物等效。     

埃索美拉唑肠溶胶囊人体生物等效性试验

目的采用高效液相色谱法测定受试者口服埃索美拉唑肠溶胶囊与埃索美拉唑镁肠溶片后血药浓度,评价埃索美拉唑肠溶胶囊的生物等效性。方法 2009年9月-10月,36例健康男性受试者单次交叉口服埃索美拉唑肠溶胶囊(试验制剂)和埃索美拉唑镁肠溶片(参比制剂),测定给药后不同时间点血浆中埃索美拉唑经时血药浓度,采用DAS 2.0软件进行药物代谢动力学参数计算和生物等效性评价。结果受试者单次口服试验制剂与参比制剂后,达峰时间分别为(2.19±0.96)、(2.43±0.92)h,峰浓度分别为(1 748.86±615.81)、(1 442.92±476.41)μg/L,药时曲线下面积(AUC)0-t分别为(3 927.14±1 839.10)、(3 878.79±1 734.84)μg/L.h,AUC0-∞分别为(3 998.36±1 866.22)、(3 918.31±1 773.44)μg/L.h。试验制剂与参比制剂的生物等效性为94.0%,其90%CI为(82.3%,107.2%)。结论埃索美拉唑肠溶胶囊与埃索美拉唑镁肠溶片生物等效。     

Bioequivalence Study of Atorvastatin Tablets in Healthy Pakistani Volunteers

A two way, randomized cross-over bioequivalence study was conducted to analyse the rate and extent of absorption of atorvastatin after a single dose of 80 mg atorvastatin as atorvastatin calcium tablets. The study was carried out using healthy male volunteers (N = 24). A high performance liquid chromatography method was employed to determine the level of drug in human plasma. It was concluded that the test and the reference drug exhibited comparable values of pharmacokinetic parameters. It was also concluded that since there was no significant difference between the rate and extent of absorption of the drug from the test and the reference formulations: these two formulations could thus be declared bioequivalent.     

洛美沙星片剂和胶囊剂的相对生物利用度研究

对９名男性健康自愿受试者单剂随机三交叉口服试验洛美沙星片和胶囊及参比胶囊４０ｍｇ后的药代动力学参数和相对生物利用度进行了比较。血、尿药浓度用ＨＰＬＣ柱切换样本直接进样法进行检测，按统计矩进行药代动力学分析。     

Pharmacokinetics of EDP-420 after Multiple Oral Doses in Healthy Adult Volunteers and in a Bioequivalence Study

EDP-420 (also known as EP-013420, or S-013420) is a first-in-class bridged bicyclolide currently in clinical development for the treatment of respiratory tract infections (RTI) and has previously shown favorable pharmacokinetic (PK) and safety profiles after the administration of single oral doses of a suspension to healthy volunteers. Here we report its PK profile after the administration of multiple oral doses of a suspension to healthy adults. Bioequivalence between suspension and capsule formulations, as well as the effect of food, is also reported. The most important PK features of EDP-420 observed in these clinical studies are its long half-life of 17 to 18 h and its high systemic exposure, which support once-daily dosing and treatment durations potentially shorter than those of most other macrolide antibiotics. EDP-420 is readily absorbed following oral administration in both suspension and capsule formulations. In the multiple-oral-dose study, steady state was achieved on day 1 by using a loading dose of 400 mg/day, followed by 2 days of 200 mg/day. A high-fat meal had no effect on the bioavailability of EDP-420 administered in a capsule formulation. EDP-420 was well tolerated, with no serious or severe adverse events reported, and no subject was discontinued from the study due to an adverse event. Based on its human PK and safety profiles, together with its in vitro/in vivo activities against common respiratory pathogens, EDP-420 warrants further development, including trials for clinical efficacy in the treatment of RTI.Macrolides are currently used as a first-line treatment for respiratory tract infections (RTIs), including community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute sinusitis, pharyngitis/tonsillitis, and otitis media (5, 37). The extensive clinical usage of macrolides has resulted in the rapid emergence of macrolide resistance, particularly among streptococci, staphylococci, and enterococci (1, 13, 38). Thus, there is an urgent need to develop new antibiotics with activity against a broad spectrum of pathogens (especially resistant strains) commonly encountered in community-acquired RTIs. The design of EDP-420 (formerly known as EP-013420, or S-013420) was undertaken in response to this unmet medical need.EDP-420 represents a novel structural class of bridged bicyclolide antibacterial agents (36) (the structure is shown in Fig. ​Fig.1).1). It exhibits potent in vitro activities against RTI pathogens, including multidrug-resistant streptococci and the atypical pathogens (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila) (4, 10, 19, 24, 27-32, 34, 39). In vivo, EDP-420 has also demonstrated efficacy against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Mycobacterium avium in mouse protection tests, against S. pneumoniae and Haemophilus influenzae in a rat lung infection model, and against penicillin- and quinolone-resistant pneumococci in a rabbit meningitis model (2-4, 22, 23, 25, 32-34). The nonclinical pharmacokinetics (PK) of EDP-420 across multiple species displayed a long half-life as well as extensive distribution and uptake into respiratory tissue and fluids (14-17, 32, 33). Moreover, EDP-420 has previously shown favorable PK and safety profiles in healthy volunteers after single oral doses given as a suspension (18). Here, the PK of EDP-420 after multiple oral suspension doses in healthy adult volunteers is reported. In addition, since a capsule formulation was developed for use in phase II clinical trials, a separate clinical study was conducted to compare the PK and safety/tolerability of two formulations (i.e., capsule versus suspension) of EDP-420 in healthy adult volunteers. The potential effects of food on the oral bioavailability and systemic exposure of EDP-420 capsules were also investigated.Open in a separate windowFIG. 1.Structures of EDP-420 (top) and its gastric acidic degradant, EDP-420 9-keto (bottom).(The results of this study were presented in part at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September 2007.)     

盐酸甲氧氯普胺片在健康人体内药动学及生物等效性评价

[目的]评价盐酸甲氧氯普胺片在健康人体内的相对生物利用度及生物等效性.[方法]采用随机、开放、双周期交叉试验设计,24名健康男性受试者分别单剂量口服2×10 mg甲氧氯普胺受试制剂或参比制剂后,在设计的时间点取静脉血,采用高效液相色谱-质谱联用法(HPLC-MS)测定甲氧氯普胺的血浆浓度,计算主要药动学参数.以方差分析方法对主要药动学参数进行均数的差别检验,以双单侧t检验进行生物等效性判定.[结果]受试者分别口服受试制剂和参比制剂后,甲氧氯普胺的主要药动学参数AUC0-24、AUC0-∞、tmax、Cmax、t1/2分别为(184.7±40.1)g/(h·L)和(174.9±36.5)g/(h·L)、(208.6±49.6)g/(h·L)和(189.1±36.9)g/(h·L)、(1.6±0.8)h和(1.2±0.4)h、(24.5±4.3)g/L和(24.4±4.4)g/L、(6.3士2.0)h和(5.0±1.2)h.受试制剂对参比制剂的相对生物利用度为(106.2±12.8)%.[结论]所建立的方法适用于盐酸甲氧氯普胺的人体药动学研究,经方差分析和双向单侧t检验证明,受试制剂与参比制剂为生物等效性制剂.     

普罗布考片单次口服给药的人体药物代谢动力学研究

目的采用高效液相色谱-质谱联用法(HPLC-MS/MS)研究普罗布考片的人体药物代谢动力学变化规律。方法 2010年10月-11月,24例健康男性受试者单次口服普罗布考片0.5 g,采用HPLC-MS/MS法测定给药后不同时间点血浆中普罗布考的经时血药浓度,采用DAS 2.0软件进行药动学参数计算。结果受试者单次口服普罗布考片,达峰时间为(11.50±6.66)h,峰浓度为(2 894.72±1 320.53)ng/mL,药-时曲线下面积(AUC)0-t为(238 876.96±131 873.67)ng/mL.h,AUC0-∞为(259 989.08±146 112.88)ng/mL.h,半衰期为(278.52±164.72)h。结论普罗布考片体内过程符合二室模型,单次口服具有较好的安全性。     

Pharmacokinetic Interaction between Ritonavir and Indinavir in Healthy Volunteers

The pharmacokinetic interaction between indinavir and ritonavir was evaluated in five groups of healthy adult volunteers to explore the potential for twice-daily (b.i.d.) dosing of this combination. All subjects received 800 mg of indinavir every 8 h (q8h) on day 2. In addition, subjects in group I received one dose of 800 mg of indinavir on day 1 and 800 mg of indinavir q8h on day 17. Subjects in Groups II and IV each received one dose of 600 mg of indinavir on days 1 and 17, and subjects in groups III and V each received one dose of 400 mg of indinavir on days 1 and 17. During days 3 to 17, ritonavir placebo or ritonavir at 200, 300, 300, or 400 mg q12h was given to groups I, II, III, IV, and V, respectively. Ritonavir at steady state probably inhibited the cytochrome P-450 3A metabolism of indinavir and substantially increased plasma indinavir concentrations, with the area under the plasma concentration-time curve (AUC) increasing up to 475% and the peak concentration in serum (C_max) increasing up to 110%. The C_max/trough concentration ratio decreased from 50 in standard q8h regimens to less than 14 when indinavir was administered with ritonavir. For a constant indinavir dose, an increase in the ritonavir dose yielded similar indinavir AUCs, C_maxs, and concentrations at 12 h (C₁₂s). For a constant ritonavir dose, an increase in the indinavir dose resulted in approximately proportional increases in the indinavir AUC, less than proportional increases in C_max, and slightly more than proportional increases in C₁₂. Ritonavir reduced between-subject variability in the indinavir AUC and trough concentrations and did not affect indinavir renal clearance. With the altered pharmacokinetic profile, indinavir likely could be given as a b.i.d. combination regimen with ritonavir. This could potentially improve patient compliance and thereby reduce treatment failures.     

Bioequivalence of 2 Azithromycin Capsule Formulations: A Randomized, Single-Dose, Open-Label, 2-Period Crossover Study in Healthy Male Pakistani Volunteers

Background

Approximately 68 brands of azithromycin capsule formulations are available in Pakistan; however, published data on their bioequivalence in the Pakistani population are not available.

Objective

Upon instructions from and approval of the Ministry of Health, Pakistan, this study was designed to evaluate the bioequivalence of a locally manufactured azithromycin capsule formulation with a reference formulation from a multinational manufacturer. This study compared dissolution profiles, relative bioavailability, and other pharmacokinetic parameters of the 2 formulations.

Methods

A single oral 500-mg dose of the 2 formulations was administered to 12 healthy adult Pakistani male volunteers under fasting conditions in a randomized, open-label, 2-period crossover study. The trial included collection of blood samples over 48 hours and a 2-week washout period. Azithromycin serum concentrations were quantified using a validated RP-HPLC/ultraviolet (UV) detection method. These results were used to determine the intended pharmacokinetic parameters. As mandated by the US Food and Drug Administration and the European Medicine Agency, the test and reference formulations were considered bioequivalent if the 90% CIs of the geometric mean ratios for the log-transformed values of their pharmacokinetic parameters were within the predetermined range of 0.8 to 1.25.

Results

When subjected to a simple model independent approach of dissolution profile comparison, f₁ (difference) and f₂ (similarity factor) were found to be 5.47 and 70.04, respectively. Similarly, the 2 azithromycin capsule formulations were well tolerated by all volunteers. Low %CV of the pharmacokinetic parameters at a sample size of 12 and significance level of 0.05 contributed to acceptable (>0.8) power of the test. The 90% CIs for the ratios of C_max, AUC_0–48, T_max, t_1/2, and mean residence time, respectively, were 0.83–0.93, 0.85–1.10, 0.86–1.08, 0.92–1.17, and 0.92–1.16.

Conclusion

This single-dose study found that test and reference formulations met the regulatory criteria for bioequivalence in these fasted, healthy male Pakistani volunteers.     

Pharmacokinetics of Cephanone in Healthy Adult Volunteers

Five volunteers received intramuscular injections of 7 mg (approximately 500 mg) of cephanone, a new cephalosporin for parenteral use per kg. Peak serum concentrations averaged 36 mug/ml, about four times as high as with the same doses of cephalothin, twice as high as with cephaloridine, and slightly lower than with cefazolin. With a constant intravenous infusion of 100 mg/h, a steady-state serum concentration of 31 mug/ml was attained in four volunteers. The serum half-life was similar for the intramuscular and intravenous studies, 2.4 and 2.6 h, respectively. Over 90% of the dose administered was recovered in the urine. The factor mainly responsible for the higher and more sustained serum concentrations of cephanone was its low renal clearance of 47 ml per min per 1.73 m(2). Cephanone has a small apparent volume of distribution, probably related to its high serum protein binding of 88%.     

A Single-Dose,Crossover-Design Bioequivalence Study Comparing Two Nicotine Gum Formulations in Healthy Subjects

Introduction

Nicotine replacement therapy (NRT) benefits smokers who wish to quit; nicotine gum represents one NRT. New formulations of nicotine gum have been developed to consider consumer preferences and needs. A new mint-flavored nicotine gum with a different texture was developed that may provide a more appealing taste and chewing experience. This study evaluated this new nicotine gum (2 and 4 mg strengths) for bioequivalence versus the original flavor sugar-free nicotine gum at corresponding dosages.

Methods

All subjects randomized in this crossover study received a single dose of all treatments, i.e., 2 and 4 mg doses of test and reference gums, separated by 2–7 days of washout between treatments. Subjects’ maximal plasma nicotine concentration (C_max) and extent of nicotine absorption (AUC_0–t) following the administration of each treatment were calculated from plasma nicotine concentrations. Ratios of test/reference for C_max and AUC_0–t were calculated to evaluate bioequivalence between the two products.

Results

Both 2 and 4 mg doses of the new mint-flavored nicotine gum were bioequivalent to the dose-matched reference product as determined by the ratio of the geometric means and their 90% confidence intervals for C_max and AUC_0–t as well as secondary pharmacokinetic parameters. The safety profiles of the test and reference gums were similar; all treatments were well tolerated.

Conclusions

A new mint-flavored nicotine gum with modified taste and texture is bioequivalent to the original flavor sugar-free nicotine gum at both the 2 and 4 mg dosage strengths and has a similar safety profile.

Funding

GlaxoSmithKline.

Trial Registration

ClinicalTrials.gov identifier NCT01847443.

     

Pharmacokinetic Properties and Bioequivalence of 2 Formulations of Valsartan 160-mg Tablets: A Randomized,Single-Dose, 2-Period Crossover Study in Healthy Korean Male Volunteers

Background

The solubility of valsartan is dependent on pH and thus may cause patient variability in drug absorption and failure in bioequivalence studies; thus, increasing the solubility and release of valsartan at low pH has been suggested for a more favorable pharmacokinetic profile. However, due to this pH dependence, the change in the formulation process could alter the disintegration and/or dissolution profile of the drug, possibly making the results of bioequivalence studies misleading.

Objective

The aim of this study was to assess the bioavailability and tolerability of a newly developed oral formulation of valsartan 160 mg (wet-granulation tablet) in healthy Korean male volunteers.

Method

This study was performed with the subjects under fasted conditions, using a randomized, single-dose, 2-period crossover design. Subjects were assigned to receive, in randomized order, a single dose of the test formulation and a reference formulation (valsartan 160-mg dry-granulation tablet), with a washout period of 7 days between the administrations. Blood samples were collected up to 24 hours after dosing, and pharmacokinetic parameters were determined after the plasma valsartan concentration was analyzed using UPLC-MS/MS. The dissolution studies of both formulations were conducted using USP apparatus 2 at 50 rpm with 1000 mL of phosphate buffer solution (pH, 6.8) at 37°C ± 0.5°C. Bioequivalence was defined per Korean Food and Drug Administration’s regulatory criteria as 90% CIs of the geometric mean test/reference ratios of AUC_0–t and C_max within the range of 0.8 to 1.25. Tolerability was assessed using physical examination and subject interviews.

Results

Sixty subjects were enrolled (mean [SD] age [range], 23.6 [2.4] years [21–31]; height, 173.7 [6.6] cm [161–190]; and weight, 68.0 [8.7] kg [54–85]). The mean AUC_0–∞ values with the test and reference tablets were 31,784 (13,844) and 32,714 (14,512) ng·h/mL, respectively; C_max, 5094 (2061) and 5064 (1864) ng/mL; T_max, 2.92 (1.04) and 3.08 (1.01) hours. The 90% CIs for the geometric mean test/reference ratios of AUC_0–t and C_max were 0.9295 to 1.0546 and 0.9190 to 1.0848, respectively, which met the criteria for bioequivalence. The most frequently reported adverse event was dizziness after blank blood sampling, recorded in 4 subjects, 2 cases each with the test and reference formulations.

Conclusions

In this study in healthy Korean male volunteers, the test and reference formulations of 160-mg valsartan met the Korean Food and Drug Administration’s regulatory criteria for bioequivalence despite the difference in formulation (wet granulation vs dry granulation). Both formulations were well tolerated, with no serious adverse events reported.     

甲苯璜酸妥舒沙星分散片在人体内的相对生物利用度

[目的]研究甲苯璜酸妥舒沙星分散片的相对生物利用度.[方法]采用随机、开放、双周期交叉试验设计.18名健康志愿者分别单剂量口服300 mg甲苯璜酸妥舒沙星片(参比制剂)或甲苯璜酸妥舒沙星分散片(受试制剂).采用HPLC法测定给药后不同时间的妥舒沙星血药浓度.[结果]参比制剂和受试制剂中的妥舒沙星Cmax分别为(927±200)μg/L、(926±210)μg/L;tmax分别为(1.17±0.24)h、(1.22±0.26)h;t1/2分别为(4.6±0.5)h、(4.4±0.5)h;AUC0～24 h分别为(4978±1284)μg/(h·L)、(5005±1349)μg/(h·L).受试制剂的相对生物利用度为(100.8±11.3)%.[结论]受试制剂与参比制剂具有生物等效性.     

A Replicate Designed Bioequivalence Study To Compare Two Fixed-Dose Combination Products of Artesunate and Amodiaquine in Healthy Chinese Volunteers

Artesun-Plus is a fixed-dose combination antimalarial agent containing artesunate and amodiaquine. The current study was conducted to compare the pharmacokinetic and safety profiles of Artesun-Plus and the WHO-designated comparator product Artesunate Amodiaquine Winthrop. To overcome the high intrasubject variability of artesunate, the study applied a two-sequence and four-period crossover (2 by 4), replicate study design to assess bioequivalence between the two products in 31 healthy male Chinese volunteers under fasting conditions. The results showed that the values of the geometric mean ratios of maximum concentration of drug in plasma (C_max) and area under the concentration-time curve from time zero to the last blood sample collection (AUC_0-last) for the artesunate component in the test and reference products were 95.9% and 93.9%, respectively, and that the corresponding 90% confidence intervals were 84.5% to 108.7% and 87.2% to 101.1%, while the geometric mean ratios for the amodiaquine component in the test and reference products were 95.0% and 100.0%, respectively, and the corresponding 90% confidence intervals were 86.7% to 104.1% and 93.5% to 107.0%. In conclusion, bioequivalence between the two artesunate and amodiaquine fixed-dose combination products was demonstrated for both components. The study also confirmed high intrasubject variability, especially for artesunate: the coefficients of variation (CV) of C_max values for the test and reference products were 39.2% and 43.7%, respectively, while those for amodiaquine were 30.6% and 30.2%, respectively.     

乳酸左氧氟沙星片剂的健康人体药代动力学和相对生物利用度研究

目的:研究乳酸左旋氧氟沙星片剂的健康人体药代动力学和相对生物利用度。方法:18名健康受试者单次,交叉口服乳酸左旋氧氟沙星片200 mg后,用HPLC-荧光法测定血浆中左氧氟沙星浓度,用BAPP2.0软件进行数据处理,计算药代动力学参数。结果:供试与参比制剂的药时曲线可用二室模型拟合,两者主要药代动力学参数Cmax分别为(2.92±0.60)μg/mL(、3.22±0.53)μg/mL;Tmax分别为(0.9±0.3)h(、0.9±0.3)h;t1/2分别为(7.27±1.02)h、(6.83±0.80)h;AUC0~24分别为(17.18±2.46)μg/(mL.h)(、17.19±2.55)μg/(mL.h),乳酸左氧氟沙星片供试制剂的相对生物利用度为(100.3±9.4)%。结论:供试与参比制剂具有生物等效性。     

Bioavailability of Edaravone Sublingual Tablet Versus Intravenous Infusion in Healthy Male Volunteers

Purpose

Edaravone is a free-radical scavenger. Edaravone 30mg IV has been approved for use in the treatment of acute ischemic stroke in Japan and China, and for amyotrophic lateral sclerosis in Japan and the United States. Considering the inconvenience of IV infusion in clinical practice, an oral tablet formulation of edaravone was developed but failed in 2011 due to poor bioavailability. More recently, a sublingual (SL) tablet formulation of edaravone 30mg was developed by a Good Manufacturing Practices–compliant manufacturer in China. This study explored the bioavailability of the SL tablet of edaravone and aimed to provide evidence to support decision making in future clinical development.

Population Pharmacokinetic and Pharmacodynamic Analysis of Polmacoxib in Healthy Volunteers and Patients With Osteoarthritis

PurposePolmacoxib, a new coxib dually inhibiting cyclooxygenase-2 and carbonic anhydrase I/II, was recently approved for osteoarthritis treatment in South Korea. This study explored the population pharmacokinetic and pharmacodynamic characteristics of polmacoxib.MethodsNonlinear mixed-effects modeling was performed using pooled pharmacokinetic data from a Phase I study in healthy individuals and pharmacokinetic properties and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) data from a Phase IIb study in patients with osteoarthritis. Pharmacodynamic models for WOMAC were sequentially fit using individual pharmacokinetic parameter estimates.FindingsPolmacoxib concentrations in whole blood were adequately described by the 2-compartment model, with mixed zero- and first-order absorption kinetics. Iron concentration was the significant covariate associated with clearance of polmacoxib. The relationship between the whole blood concentration of polmacoxib and WOMAC was best described by a 2-effect compartment model that consisted of central and peripheral compartments with the rate constant of 0.408 min^?1 for distribution to the central effect compartment. A decrease in WOMAC was linked to the central effect site compartment concentration through an ordinary maximum effect model with an effect site concentration needed to achieve 50% of the maximum effect of 508 ng/mL.ImplicationsThe current model accurately characterized the pharmacokinetic and pharmacodynamic properties of polmacoxib and could provide a basis for individualized drug therapy.     

Pharmacokinetic Interactions between Primaquine and Pyronaridine-Artesunate in Healthy Adult Thai Subjects

Pyronaridine-artesunate is a newly introduced artemisinin-based combination treatment which may be deployed together with primaquine. A single-dose, randomized, three-sequence crossover study was conducted in healthy Thai volunteers to characterize potential pharmacokinetic interactions between these drugs. Seventeen healthy adults received a single oral dose of primaquine alone (30 mg base) and were then randomized to receive pyronaridine-artesunate alone (540−180 mg) or pyronaridine-artesunate plus primaquine in combination, with intervening washout periods between all treatments. The pharmacokinetic properties of primaquine, its metabolite carboxyprimaquine, artesunate, its metabolite dihydroartemisinin, and pyronaridine were assessed in 15 subjects using a noncompartmental approach followed by a bioequivalence evaluation. All drugs were well tolerated. The single oral dose of primaquine did not result in any clinically relevant pharmacokinetic alterations to pyronaridine, artesunate, or dihydroartemisinin exposures. There were significantly higher primaquine maximum plasma drug concentrations (geometric mean ratio, 30%; 90% confidence interval [CI], 17% to 46%) and total exposures (15%; 6.4% to 24%) during coadministration with pyronaridine-artesunate than when primaquine was given alone. Pyronaridine, like chloroquine and piperaquine, increases plasma primaquine concentrations. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01552330","term_id":"NCT01552330"}}NCT01552330.)