OATP1B1 388A>G polymorphism and pharmacokinetics of pitavastatin in Chinese healthy volunteers

Purpose: To investigate the contribution of the most frequent single nucleotide polymorphism (SNPs) of the organic anion transporting polypeptide 1B1 (OATP1B1) 388A>G to the pharmacokinetics of pitavastatin in Chinese healthy volunteers. Methods: Eighteen healthy volunteers participated in this study. Group 1 consisted of nine subjects who were of 388AA wild‐type OATP1B1 genotype. Group 2 consisted of seven subjects with the 388GA genotype and two 388GG homozygotes. Two milligram of pitavastatin was administered orally to the volunteers. The plasma concentration of pitavastatin was measured for up to 48 h by liquid chromatography–mass spectrometry (LC–MS). Results: The pharmacokinetic parameters of pitavastatin were significantly different between the two genotyped groups. The concentration (C_max) value was higher in the 388GA + 388GG group than that in the 388AA group (39·22 ± 8·45 vs. 22·90 ± 4·03 ng/mL, P = 0·006). The area under the curve to the last measurable concentration (AUC_0–48) and area under the curve extrapolated to infinity (AUC_0–∞) of pitavastatin were lower in the 388AA group than in the 388GA + 388GG group (100·42 ± 21·19 vs. 182·19 ± 86·46 ng h/mL, P = 0·024; 108·12 ± 24·94 vs. 199·64 ± 98·70ng h/mL, P = 0·026) respectively. The oral clearance (Cl/F) was lower in the 388GA + 388GG group than that in the 388AA group (12·46 ± 4·79 vs. 19·21 ± 3·74/h, P = 0·012). The elimination of half‐life (t_1/2) and peak concentration times (T_max) values showed no difference between these groups. Conclusions: The OATP 388A>G polymorphism causes significant alterations in the pharmacokinetics of pitavastatin in healthy Chinese volunteers and this may well be clinically significant.     

Pharmacogenetic determinants for interindividual difference of tacrolimus pharmacokinetics 1 year after renal transplantation

What is known and objective: Tacrolimus, a widely used immunosuppressive agent in organ transplantation, has a narrow therapeutic window. It has been suggested that its interaction with lansoprazole could be dependent on polymorphisms of CYP3A5 and CYP2C19. The objective of this study was to investigate how, 1 year after renal transplantation, CYP3A5 and CYP2C19 polymorphisms, biochemical parameters and coadministration with lansoprazole, influenced tacrolimus pharmacokinetics. Methods: The pharmacokinetics of tacrolimus was studied 1 year after renal transplantation, in 75 recipients who were all receiving continuation treatment with 12‐hourly oral tacrolimus, and 30 mg lansoprazole daily (Group 1; n = 20) or, 10 mg rabeprazole daily or no proton pump inhibitor (Group 2; n = 55). Results: There were no significant differences in the dose‐adjusted area under the plasma concentration–time curve (AUC_0–12) and maximum plasma concentration (C_max) of tacrolimus between CYP2C19 genotype groups, but there were significant differences between CYP3A5 genotypes groups (*1/*1 + *1/*3 vs. *3/*3 = 45·2 ± 20·0 vs. 71·0 ± 34·1 ng·h/mL/mg, P < 0·0001 and 6·3 ± 2·6 vs. 9·3 ± 7·0 ng/mL/mg, P = 0·0017, respectively) and between co‐administration with and without lansoprazole (74·5 ± 34·0 vs. 52·4 ± 27·4 ng·h/mL/mg, P = 0·0054 and 10·9 ± 8·8 vs. 6·7 ± 3·0 ng/mL/mg, P = 0·0024, respectively). In a multiple regression analysis, the dose‐adjusted AUC_0–12 and C_max of tacrolimus were associated with CYP3A5*3/*3 and co‐administration with lansoprazole. What is new and conclusion: CYP2C19 does not seem to contribute to the interaction between tacrolimus and lansoprazole. The long‐term combination of tacrolimus and lansoprazole requires careful monitoring of patients with the CYP3A5*3/*3 genotype.     

Effect of plasma uric acid on pharmacokinetics of cyclosporine A in living‐related renal transplant recipients and pharmacokinetic study in rats with experimental hyperuricaemia

Objectives: Renal transplant recipients are thought to have an increased risk of hyperuricaemia (HU); therefore, the effects of plasma uric acid (UA) on the pharmacokinetics (PK) of cyclosporine A (CyA), an immunosuppressant, in renal transplant recipients and experimental animals were investigated. Methods: An open‐label, non‐randomized, retrospective study was performed in renal transplant recipients. Data from 76 subjects who received a renal transplantation with CyA medication were included. We compared the PK of CyA of recipients showing a high UA level with the other recipients. In addition, PK studies were performed using hyperuricaemic‐model rats (HU rats) prepared by subcutaneous injection of the uricase inhibitor, potassium oxonate and intraperitoneal injection of UA. Results: The area under the blood concentration vs. time curve (AUC) up to 9 h, the blood level at 2 h after dose and peak level in high UA recipients (UA > 7·0 mg/dL) was significantly lower (about 10–16%) than that in the other recipients, although there were no differences in dose, and the trough blood level. On the contrary, there were no differences in PK parameters after intravenous administration of CyA between HU and control rats; however, AUC, peak level and bioavailability in HU rats (2·01 ± 0·56 μg h/mL, 0·47 ± 0·26 μg/mL and 0·186 ± 0·05, respectively) after oral administration were significantly lower than in the control animals (6·13 ± 0·97 μg h/mL, 0·82 ± 0·17 μg/mL and 0·458 ± 0·07 μg/mL, respectively). In addition, the absorptions of CyA and midazolam, an ideal probe for CYP3A, from the intestinal loop in HU rats were significantly less (about 50% and 37%, respectively) than in the controls. Conclusions: The absorption of CyA was affected by plasma UA in transplant recipients and experimental rats. The contribution of intestinal metabolism by CYP3A to decreasing CyA absorption in HU rats was significant. These results suggest that transplant recipients with high UA may have poor absorption of CyA.     

Influence of CYP2D6*10 on the pharmacokinetics of metoprolol in healthy Korean volunteers

Background and objective: Genetic polymorphism of CYP2D6 leads to differences in pharmacokinetics of CYP2D6 substrates. The CYP2D6*10 allele is clinically important in Koreans because of its high frequency in Asians. We investigated whether the pharmacokinetics of metoprolol was altered by the presence of the CYP2D6*10 allele in Korean subjects. Methods: One hundred and seven volunteers were recruited and grouped as CYP2D6*1/*1, CYP2D6*1/*10 and CYP2D6*10/*10 according to their genotypes. Metoprolol tartrate 100 mg (Betaloc^®) was administered orally once to each subject in these three groups (n = 6, 7 and 5, respectively). The pharmacokinetic parameters of metoprolol and its metabolite, α‐hydroxymetoprolol, and the metabolic ratio for the three groups were estimated and compared. Results and discussion: The area under the plasma concentration–time curve (AUC_0→∞), the maximum plasma concentration (C_max) and the elimination half‐life (T_1/2) of metoprolol and α‐hydroxymetoprolol for the CYP2D6*10/*10 group were all significantly different from those of the CYP2D6*1/*1 group (P < 0·05). The AUC_0→∞s of metoprolol were 443·7 ± 168·1, 995·6 ± 321·4 and 2545·3 ± 632·0 ng·h/mL, and the AUC_0→∞s of α‐hydroxymetoprolol were 1232·0 ± 311·2, 1344·0 ± 288·1 and 877·4 ± 103·4 ng·h/mL for groups CYP2D6*1/*1, *1/*10 and *10/*10, respectively. The corresponding T_1/2 values of metoprolol were 2·7 ± 0·5, 3·2 ± 1·3 and 5·0 ± 1·1 h, while those of α‐hydroxymetoprolol were 5·4±1·5, 6·0 ± 1·4 and 10·5 ± 4·2 h, respectively. The metabolic ratios of the three groups were significantly different (P < 0·05). Conclusion: The CYP2D6*10 allele altered the pharmacokinetics of metoprolol in Korean subjects and is likely to affect other drugs metabolized by the CYP2D6 enzyme, similarly.     

Pharmacokinetics of single‐dose rosiglitazone in chronic ambulatory peritoneal dialysis patients

Background: End‐stage renal disease (ESRD) is associated with marked alterations in the pharmacokinetics of many drugs, not only from reduction in renal clearance but also from changes in metabolic activity, bioavailability, volume of distribution and plasma protein binding. Objective: To study the pharmacokinetics of a single 8‐mg oral dose of rosiglitazone in patients with ESRD and requiring long‐term chronic ambulatory peritoneal dialysis (CAPD). Method: The medication was administered just before the first exchange of peritoneal dialysis fluid on the day that blood and peritoneal dialysate collection was performed. Results: In our CAPD patients the mean (±SD) T_max and T_1/2 of rosiglitazone were 1·20 ± 0·26 and 21·38 ± 21·96 h respectively. These values were different to those reported for healthy volunteers reported in previous studies. The mean area under the concentration–time curve (AUC_(0–∞)) and an average maximum observed plasma concentration (C_max) of rosiglitazone in our CAPD patients were 4203·56 ± 2916·97 ng h/mL and 409·67 ± 148·89 ng/mL respectively. These appear no different from those reported in healthy volunteers . Conclusion: The apparently significant difference in T_1/2 of rosiglitazone in CAPD patients compared with healthy volunteers suggest that dose adjustment may be necessary in order to avoid toxicity.     

Effect of telmisartan, valsartan and candesartan on mycophenolate mofetil pharmacokinetics in Japanese renal transplant recipients

Objective: The aim of this study was to elucidate the effect of the peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) activating angiotensin receptor blocker (ARB) telmisartan and the non‐PPAR‐γ activating ARB valsartan and candesartan on mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients. Methods: Recipients (n = 10 each group) were randomly given either 40 mg of telmisartan, 80 mg of valsartan or 8 mg of candesartan cilexetil for at least 6 months, and no ARB. Blood was sampled a year after transplantation. Results: Dose‐adjusted maximum and trough plasma concentration of MPA co‐administered with telmisartan were the lowest in all groups. The mean dose‐adjusted area under the concentration curve from 0 to 12 h (AUC_0–12) and AUC_0–6 of MPA co‐administered with telmisartan were significantly lower than that without ARB (98 vs. 138 ng·h/mL/mg, P = 0·0353 and 63 vs. 96 ng·h/mL/mg, P = 0·0305). Coadministration of valsartan and candesartan did not alter MPA pharmacokinetics. The AUC ratio of MPA glucuronide (MPAG)/MPA co‐administered with telmisartan was higher than that without ARBs, but not significantly (14·2 vs. 9·1). The mean maximum and minimum plasma concentrations of telmisartan (40 mg) after oral administration were 84 and 15 ng/mL, respectively, and that of valsartan (80 mg) 2220 and 441 ng/mL, respectively. Plasma concentrations of candesartan in most transplant patients were not observed 19 h after oral administration of candesartan cilexeil (8 mg). Conclusions: The degree of drug interaction between MPA and telmisartan was significantly greater than that between MPA and valsartan or candesartan. Uridine diphosphate‐glucuronosyltransferase (UGT) 1A9 has been identified as a PPAR‐γ target gene. UGT induction by telmisartan might stimulate MPA glucuronidation. A combination of telmisartan and mycophenolate mofetil might require periodic monitoring of MPA.     

Whole saliva and plasma levels of clozapine and desmethylclozapine

Background: Therapeutic drug monitoring of clozapine as an aid in the treatment of schizophrenic states is commonly used in our hospital. Objective: Development of a high-performance liquid chromatographic method for the deter?mination of clozapine (CLZ) and its major metabolite desmethylclozapine (DMCLZ) in plasma and saliva, and investigation of the relationship between plasma concentrations of CLZ and DMCLZ and concentrations in saliva in patients treated with clozapine. Methods: Subjects were either inpatients or outpatients with a DSM IV diagnosis of schizophrenia ( n=34). Determination of CLZ and DMCLZ saliva concentrations appeared to be a satisfactory method to check compliance to treatment, particularly in outpatients. Results: Mean CLZ and DMCLZ plasma concentrations were 432±264 ng/ml (±SD) (range 90–1310 ng/ml) and 257±144 ng/ml (range 55–580 ng/ml), respectively. The CLZ/DMCLZ plasma ratio was equal to 1·7±0·5 (daily dosage 7·2±2·3 mg/kg, n=34). Mean CLZ plasma and saliva levels were 336±157 ng/ml (range 90–580 ng/ml) and 159±86 ng/ml (range 40–364 ng/ml), respectively ( r=0·56, n=14). Mean DMCLZ plasma and saliva levels were 196±112 ng/ml (range 55–481 ng/ml) and 109±67 ng/ml (range 40–250 ng/ml), respectively ( r=0·73, n=14). Mean CLZ/DMCLZ ratios determined in plasma and saliva were 1·9±0·6 (range 1·0–3·4) and 1·7±0·6 (range 1·0–3·2), respectively ( r=0·85, n=14). CLZ and DMCLZ saliva concentrations appear to be useful for checking compliance to treatment, in particular among outpatients.     

Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel

Background and objectives: Clopidogrel is an important antiplatelet drug that is effective in preventing thrombotic events, especially for patients undergoing percutaneous coronary intervention. The therapeutic usefulness of clopidogrel has been limited by documented inter‐individual heterogeneity in platelet inhibition, which may be attributable to known clopidogrel pharmacokinetic variability. The objective of this study was to assess the influence of smoking cigarettes and abnormal body weight on the pharmacokinetics of clopidogrel. Methods: Seventy‐six healthy adult male volunteers were selected randomly. Each subject received a single 75 mg oral dose of clopidogrel after overnight fast. Clopidogrel carboxylate plasma levels were measured and non‐compartmental analysis was used to determine peak plasma concentration (C_max), time to peak plasma concentration (T_max), elimination half‐life (t_1/2e), and area under the curve (AUC_0→∞). Results: One‐third of volunteers were smokers (n = 27) and one‐half had abnormal body weight (n = 39). Smokers had lower AUC_0→∞ (smokers: 6·24 ± 2·32 μg/h/mL vs. non‐smokers: 8·93 ± 3·80 μg/h/mL, P < 0·001) and shorter half‐life (smokers: 5·46 ± 2·99 vs. non‐smokers: 8·43 ± 4·26, P = 0·001). Smoking behaviour had no influence on C_max (P = 0·3) and T_max (P = 0·7). There was no statistically significant difference in C_max, AUC_0→∞, T_max and t_1/2e between volunteers with abnormal body weight and normal body weight. However the difference in body weight of the two groups was relatively narrow (mean ± SE; 26·93 ± 0·16 vs. 23·11 ± 0·27). In general, the pharmacokinetic parameters were characterized by considerable inter‐individual differences (C_max = 3·09 ± 0·99 μg/mL, CV = 32%), (T_max =0·76 ± 0·24 h, CV = 31·6%), (AUC_0→∞ = 7·98 ± 3·58 μg/h/mL, CV = 44·8%), and (t_1/2e = 7·38 ± 4·10 h, CV = 55·6%). Conclusion: Smoking is a significant factor affecting the pharmacokinetics of clopidogrel, following administration of a single 75 mg dose in healthy young volunteers. The study supports smoking‐cessation recommendations. Further studies are required to evaluate the influence of smoking and body weight on the pharmacokinetics of the active metabolite of clopidogrel and on the clinical effects of any differences observed.     

The Pharmacokinetics,Efficacy, Safety,and Ease of Use of a Novel Portable Metered-Dose Cannabis Inhaler in Patients With Chronic Neuropathic Pain: A Phase 1a Study

ABSTRACT

Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a “main stream” pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ⁹-tetrahydrocannabinol (THC) and 11-hydroxy-Δ⁹-THC were taken at baseline and up to 120 minutes. Pain intensity (0–10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ⁹-THC plasma C_max ± SD was 38 ± 10 ng/mL, T_max ± SD was 3 ± 1 minutes, AUC_0→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma C_max increase per mg Δ⁹-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of C_max (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15–30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ⁹-THC pharmacokinetic profile with low interindividual variation of C_max, achieving pharmaceutical standards for inhaled drugs.     

Pharmacokinetics and safety of low-dose submicron indomethacin 20 and 40 mg compared with indomethacin 50 mg

Introduction. Indomethacin is a potent analgesic that, similar to other nonsteroidal anti-inflammatory drugs, is associated with serious dose-related adverse events. There is a need for newer nonsteroidal anti-inflammatory drug products with improved tolerability. Low-dose submicron indomethacin was developed using SoluMatrix Fine Particle Technology? to enable treatment at lower doses than commercially available indomethacin drug products. This study evaluated the pharmacokinetics and safety of submicron indomethacin 20 and 40 mg compared with indomethacin 50-mg capsules. Methods. This was a phase 1, randomized, open-label, 4-period, 4-sequence, single-dose crossover study. Forty healthy volunteers received low-dose submicron indomethacin 20- or 40-mg capsules, or indomethacin 50-mg capsules under fasting or fed conditions. Pharmacokinetic parameters and safety were assessed. Results. Comparable fasting peak plasma levels (mean ± standard deviation) were demonstrated for submicron indomethacin 40 mg (2368.79 ± 631.38 ng/ml) and indomethacin 50 mg (2369.40 ± 969.06 ng/ml). The overall systemic exposure (geometric least squares mean; 95% CI) was > 21% lower for submicron indomethacin 40 mg (6007.71 ng·h/mL; 5585.73–6461.58) compared with indomethacin 50 mg (7646.23 ng·h/ml; 7110.44–8222.40) under fasting conditions. Food delayed the rate but did not affect the extent of indomethacin absorption from submicron indomethacin 40 mg. Submicron indomethacin 40 mg administration resulted in earlier time to peak plasma levels (median 1.67; min–max 0.5–3.5 hours) under fasting conditions compared with indomethacin 50 mg (2.02; 0.5–5.0 hours). Submicron indomethacin 20 and 40 mg were dose proportional and generally well tolerated. Conclusion. Compared with indomethacin 50 mg, submicron indomethacin 40 mg achieved similar peak plasma concentrations, lower systemic exposure, and a faster time to peak plasma concentration, indicating rapid absorption. The current formulation of low-dose submicron indomethacin has recently demonstrated efficacy in 2 phase 3 studies in patients with acute pain following bunionectomy and represents a new, low-dose treatment option for patients with acute pain.     

Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers

Background and objective: CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. Methods: Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography–tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post‐dose. Results and discussion: There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC_0–∞ and C_max in group C were significantly higher [83·94 ± 40·41 vs. 16·39 ± 5·10 μg·h/mL (P = 0·000) and 1·50 ± 0·85 vs. 0·45 ± 0·18 μg/mL (P = 0·000)], and the oral clearance was significantly lower [1·17 ± 0·63 vs. 5·38 ± 1·86 L/h (P = 0·000)]. The half‐life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33·47 ± 12·39 vs. 19·34 ± 10·45 h), but the difference was not significant (P = 0·052). The increase in serum glucose level at 11 h after dosing (ΔC_glu11) in group C was significantly higher than that of group A (?1·08 ± 0·42 vs. 0·22 ± 1·01 mmol/L, P = 0·022). The corresponding insulin levels showed no difference between the two groups. Conclusion: CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result.     

Drug interaction between St John's wort and zolpidem in healthy subjects

What is known and objective: St John’s wort (SJW, Hypericum perforatum) is one of the most commonly used herbal antidepressants for treatment of mild to moderate depression. SJW enhances CYP3A4 activity and alters the pharmacokinetics of CYP3A4 substrates. This study investigated the effect of SJW on the pharmacokinetics of zolpidem in healthy subjects. Methods: A controlled, open‐label, non‐randomized, fixed‐dose schedule design was used. Fourteen healthy male subjects received a single 10 mg oral dose of zolpidem followed by SJW administration (300 mg orally, three times a day) for 14 days; the last dose of SJW was coadministered with a single dose of zolpidem. Blood samples were obtained over a 24‐h period after zolpidem administration. Pharmacokinetic data for zolpidem alone and in combination with SJW were analysed by high‐performance liquid chromatography. Results: After repeated administration of SJW, the mean values of AUC and C_max for zolpidem significantly decreased (380·3 ± 181·4 vs. 265·4 ± 134·2 ng h/mL, P = 0·001; 83·1 ± 30·1 vs. 55·1 ± 24·8 ng/mL, P = 0·000 respectively) and the mean value of CL/F for zolpidem significantly increased (38·4 ± 31·5 vs. 56·9 ± 57·2 mL/min, P = 0·040). However, in three subjects, the AUC showed a small increase after SJW treatment. What is new and conclusion: The effect of SJW on the pharmacokinetics of zolpidem has not previously been reported. Repeated administration of SJW decreases the plasma concentration of zolpidem, probably by enhancing CYP3A4 activity. Given the wide inter‐subject variability observed, for personalized medicine, advice on the use of the combination should be individualized, based on the circumstances of the patient.     

A Phase I Study Evaluating the Pharmacokinetic Profile of a Novel,Proprietary, Nano-formulated,Lower-Dose Oral Indomethacin

Abstract

Background: Safety and tolerability concerns associated with nonsteroidal anti–inflammatory drugs (NSAIDs) have prompted the development of lower–dose formulations. This phase 1 clinical study characterizes the pharmacokinetic (PK) profile of an investigational, proprietary, nano–formulated, lower–dose oral indomethacin (nano–formulated indomethacin) compared with standard oral indomethacin in healthy subjects. Methods: Forty healthy subjects were enrolled in a single–dose, randomized, 5-period, 5-treatment crossover study. Subjects received nano–formulated indomethacin 20 mg (fasted), or nano–formulated indomethacin 40 mg or standard indomethacin 50 mg (fed and fasted). Pharmacokinetic parameters, including maximum measured plasma concentration (C_max), time to maximum measured concentration (T_max), elimination half–life (T_1/2), and area under the concentration–time (AUC) curve, along with safety and tolerability, were assessed. Results: There was a more rapid mean (± standard deviation) T_max for nano–formulated indomethacin 20 mg (1.11 ± 0.55 h) and 40 mg (1.25 ± 0.60 h) compared with indomethacin 50 mg (1.97 ± 0.81 h) under fasting conditions, demonstrating faster absorption for the nano–formulated indomethacin. The T_1/2 was similar for nano–formulated indomethacin 40 mg and indomethacin 50 mg. The C_max for nano–formulated indomethacin 40 mg was higher compared with indomethacin 50 mg in fasted subjects (3115 ± 900 ng/mL vs 2759 ± 936 ng/mL, respectively), and slightly lower in fed subjects (1360 ± 424 ng/mL vs 1408 ± 469 ng/mL, respectively). There was a 26% reduction in drug exposure (AUC_0-∞) when subjects received nano–formulated indomethacin 40 mg compared with indomethacin 50 mg under fasting conditions (6861 ± 1585 h*ng/mL vs 9306 ± 2234 h*ng/mL, respectively). Safety and tolerability were comparable between formulations. Conclusion: The nano–formulated, lower–dose indomethacin had an improved PK profile compared with indomethacin. Under the advisory issued by worldwide regulatory agencies regarding use of lowest effective doses, these data may support use of lower–dose NSAID formulations that improve safety/tolerability while maintaining pain relief similar to standard NSAID formulations.     

Excessive exercise ventilation in moderate left heart dysfunction. Influence of postural changes in central haemodynamics and blood gases

To evaluate the relative importance of pulmonary congestion and peripheral hypoxia as causes for the excessive exercise ventilation in left heart dysfunction, seven patients with excessive ventilation and distinct left heart dysfunction during moderate exercise (LHD), and seven control patients with essentially normal exertional functions (CTR), had ventilation, central haemodynamics, arterial and mixed venous blood gases examined at rest and exercise, 32 W (25–40) in the LHD group and 44 W (33–49) in the CTR group, in lying and sitting positions. Change from lying to sitting exercise, led to fall in pulmonary artery wedge pressure (PAWP) from 31·0 ± 5·5 to 8·8 ± 5·0 mmHg in the LHD group, compared with from 13·7 ± 1·0 to 2·1 ± 2·4 mmHg in the controls, while ventilation/O₂ intake ratio (V˙/V˙O₂) and physiological dead space/tidal volume ratio (V_D/V_T) showed a tendency to rise, from 36·3 ± 8·8 to 39·2 ± 7·4, and from 0·35 ± 0·11 to 0·39 ± 0·09, respectively, in the LHD group, and from 27·5 ± 3·1 to 28·7 ± 5·3, and from 0·19 ± 0·09 to 0·21 ± 0·12 in the controls. Mixed venous O₂ tension (PvO ₂) showed a marked decline from 3·60 ± 0·33 to 3·26 ± 0·36 kPa in the LHD group, as compared with from 3·94 ± 0·28 to 3·71 ± 0·29 kPa in the controls, while the calculated physiologic shunt (Q˙_s/Q˙_t) suggested improved alveolo‐arterial gas exchange. The data fit in with recent studies ascribing the excessive exercise ventilation to a combination of signals from hypoxia‐induced changes, particularly in the exercising muscles, and augmented ergoreflex and central and peripheral chemoreceptor activity, partly to changes in the integrated control of ventilation and circulation, not to mechanisms related to pulmonary congestion.     

Plasma and urinary leukotrienes in sickle cell disease: possible role in the inflammatory process

Abstract. Sickle cell (HbSS) disease is associated with rheological and inflammatory stresses within the microcirculation. In order to determine the role of leukotrienes in the inflammatory processes in HbSS patients, we analysed plasma and urine levels of leukotrienes (LT); LTB₄, LTC₄, LTD₄, and LTE₄ as indicators of their in vivo metabolism. Plasma and urine level samples of 15 HbSS patients in steady-state and age-matched healthy, homozygous (HbAA) controls were extracted for leukotrienes and quantitated by HPLC. Control plasma level of leukotrienes (mean ± SEM, ng ml^-1) were: LTB₄, 8·95 ± 0·26; LTC₄, 7·24 ± 0·21; LTD₄, 11·42 ± 0·40; and LTE₄, 14·51 ± 0·50. Corresponding values for HbSS patients were: LTB₄, 6·15 ± 0·42; LTC₄, 13·61 ± 1·45; LTD₄, 6·44 ± 0·51 and LTE₄, 4·97 ± 0·37. The differences were significant at P < 0·05. Urine levels (mean ± SEM, ng mmol^-1 creatinine), for controls were: LTB₄, 10·60 ± 0·35; LTC₄, 360·0 ± 9·82. Values for HbSS urine were: LTB₄, 27·50 ± 3·33; LTC₄, 356·0 ± 17·87; LTD₄, 69·90 ± 14·51. LTD₄ was not detected in control urine. These results suggest that sickle cell patients may exhibit impaired ability to catabolize LTC₄ in plasma during steady state conditions. This altered metabolism may contribute to the persistent stress of the microcirculation, and is probably related to the abnormal microvascular rheology of sickle blood cells.     

A pharmacokinetic comparison of single doses of once-daily cyclobenzaprine extended-release 15 mg and 30 mg: A randomized,double-blind,two-period crossover study in healthy volunteers

Objective: The purpose of this study was to compare the pharmacokinetics and tolerability of single oral doses of cyclobenzaprine extended-release (CER) 15- and 30-mg capsules.Methods: This was a randomized, double-blind, 2-period crossover study in healthy adults aged 18 to 40 years. Subjects were assigned to receive a single dose of either CER 15 mg or 30 mg on days 1 and 15, separated by a 14-day washout. Study comparisons included the plasma cyclobenzaprine AUC to 168 hours after dosing (AUC_0–168), AUC_0–∞, and C_max. Plasma cyclobenzaprine T_max, terminal elimination t_1/2, and adverse events (AEs) were also assessed.Results: Sixteen subjects (9 women, 7 men) were randomized to receive cyclobenzaprine 15 mg or 30 mg; 13 (81.3%) were white and 3 (18.8%) were black. Mean age and weight were 30.2 years and 70.7 kg, respectively. The shapes of the pharmacokinetic profiles for CER 15 and 30 mg were parallel. Mean observed values for dose-dependent pharmacokinetic parameters of CER 15 and 30 mg were as follows: AUC_0–168, 318.3 and 736.6 ng · h/mL, respectively; AUC_0–∞), 354.1 and 779.9 ng · h/mL; and C_max, 8.3 and 19.9 ng/mL. Dose-independent parameters were comparable across doses. Median observed Tmax was 6.0 hours for both CER doses; mean t_1/2 was 33.4 hours for CER 15 mg and 32.0 hours for CER 30 mg. The bioavailability of the 2 doses, as indicated by the least squares mean AUC_0–∞, was 330.3 ng · h/mL for CER 15 mg and 755.1 ng · h/mL for CER 30 mg. During the CER 15-mg treatment sequence, 5 subjects experienced 5 AEs (headache, dizziness, musculoskeletal pain, dermatitis, and glossodynia); during the CER 30-mg treatment sequence, 2 subjects experienced 2 AEs (somnolence and dysmenorrhea). All AEs were mild in intensity. No serious AEs occurred during the study.Conclusions: Once-daily CER 15 and 30 mg exhibited similarly shaped pharmacokinetic profiles. AUC_0–168, AUC_0–∞), and C_max values for the 30-mg dose were approximately double those for the 15-mg dose, a result consistent with previously reported data on the dose proportionality of cyclobenzaprine immediate release.     

Pharmacokinetics and safety of bromotetrandrine (BrTet, W198) after single-dose intravenous administration in healthy Chinese volunteers

Objective: To investigate the safety and pharmacokinetics of bromotetrandrine (BrTet, W198), a novel inhibitor of P‐glycoprotein (P‐gp), after single‐dose i.v. infusion in healthy Chinese volunteers. Methods: We conducted a randomized, dose‐escalating, phase I clinical study for that purpose. Thirty healthy subjects received BrTet at the doses of 10, 20 or 30 mg/m² by i.v. infusion. Plasma and urine concentrations of bromotetrandrine were determined by using a liquid chromatography–tandem mass spectrometric (LC/MS/MS) method. AUC was calculated by the trapezoidal rule extrapolation method. C_max, T_max, t_1/2α, t_1/2β, Cl and V_d were compiled from the plasma concentration–time data. Results: Bromotetrandrine was generally well tolerated at all doses. No serious or severe adverse events were found in the study. The pharmacokinetic parameters of BrTet after single i.v. infusion doses of BrTet 10, 20 and 30 mg/m² were as follows: T_max were 1·5 h in three groups, C_max were 24·79, 39·59 and 64·31 μg/L, t_1/2α were 0·37, 0·29 and 0·30 h, t_1/2β were 62·88, 56·45 and 52·20 h. AUC_0–194h were 345·83, 688·15 and 1096·28 μg h/L, Cl were 23·68, 25·69 and 25·66 L h/m², V_d were 157·73,156·96 and 140·73 L/m². In urine, the total eliminate rate of originate compound was 0·61 ± 0·19%. Conclusions: This study suggested that bromotetrandrine was well tolerated in healthy volunteers within the dose range evaluated. The pharmacokinetics parameters of bromotetrandrine indicated that the compound was rapidly distributed and accumulated in the tissues, and slowly cleared from plasma, which supported the use of BrTet for a once or twice dosing per chemotherapy cycle.     

Effective plasma concentrations of mycophenolic acid and its glucuronide in systemic lupus erythematosus patients in the remission-maintenance phase

What is known and Objective: Mycophenolate mofetil (MMF) has been reported recently to be effective in the treatment of systemic lupus erythematosus (SLE). The therapeutic range of mycophenolic acid (MPA) in SLE in the remission‐maintenance phase remains to be clarified. The aim of this study was to evaluate the therapeutic efficacy of MMF and predose plasma concentrations of MPA and its phenolic glucuronide (MPAG) in patients with SLE in the remission‐maintenance phase. Methods: Thirty‐one patients with SLE receiving a fixed dosage regimen of MMF (median and interquartile range, 1500 and 1000–2000 mg/day) for at least 1 month and who had not experienced any adverse drug reactions for more than 3 months were enrolled. Results: Significant improvement was observed after MMF administration in total haemolytic complement CH₅₀ and its fractions C3 and C4, immunoglobulins IgG, IgA and IgM, anti‐dsDNA antibody, serum concentration of albumin and red blood cell count, even though the mean daily dose of prednisolone was significantly reduced (P = 0·02). Median predose plasma concentrations of MPA and MPAG were 1·95 and 26·2 μg/mL (interquartile ranges, 0·94–2·96 and 18·6–53·7 μg/mL). Predose plasma concentrations of MPA and MPAG correlated significantly with MMF dose (r = 0·64, P < 0·01 and r = 0·39, P = 0·03). What is new and Conclusions: MMF improved clinical laboratory markers and reduced prednisolone dosage in SLE patients with predose plasma concentration of MPA and MPAG in the interquartile ranges of 0·94–2·96 and 18·6–53·7 μg/mL, respectively.     

Pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers

What is known and Objective: Ivabradine is a novel heart rate‐lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Our objective was to evaluate a possible pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers. Methods: The study consisted of two periods: Period 1 (Reference), when each volunteer received a single dose of 10 mg ivabradine and Period 2 (Test), when each volunteer received a single dose of 10 mg ivabradine and 400 mg carbamazepine. Between the two periods, the subjects were treated for 15 days with a single daily dose of 400 mg carbamazepine. Plasma concentrations of ivabradine were determined during a 12‐h period following drug administration, using a high‐throughput liquid chromatography with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment period were calculated using non‐compartmental and compartmental analysis to determine if there were statistically significant differences. Results and Discussion: In the two periods of treatments, the mean peak plasma concentrations (C_max) were 16·25 ng/mL (ivabradine alone) and 3·69 ng/mL (ivabradine after pretreatment with carbamazepine). The time taken to reach C_max, t_max, were 0·97 and 1·14 h, respectively, and the total areas under the curve (AUC_0‐∞) were 52·49 and 10·33 ng h/mL, respectively. These differences were statistically significant for C_max and AUC_0‐∞ when ivabradine was administered with carbamazepine, whereas they were not for t_max, half‐life and mean residence time. What is new and Conclusion: TCarbamazepine interacts with ivabradine in healthy volunteers, and lowers its bioavailability by about 80%. This magnitude of effect is likley to be clinically significant.     

Pharmacokinetics of midazolam tablet in different Chinese ethnic groups

What is known and Objectives: Subjects of different ethnic groups may respond differently to drugs. The present study was conducted to compare the oral pharmacokinetics of midazolam among healthy volunteers from five different ethnic groups in China: Han, Mongolian, Uygur, Hui and Korean. Methods: Healthy volunteers (10 Hans, 10 Mongolians, 10 Uygurs, 10 Huis and 9 Koreans) of Chinese nationality received a single oral tablet dose of 15 mg midazolam in an open label, parallel‐group study. Blood samples were collected at intervals and analysed for midazolam by high performance liquid chromatography (HPLC). Ethnic differences in pharmacokinetic parameters of midazolam using non‐compartmental methods and anova and Kruskal–Wallis rank test. Results and Discussion: Midazolam maximum concentration (C_max) was significantly lower in Mongolians than that in Hans, Uygurs, Huis and Koreans (74·9 ± 33·7, 103·1 ± 26·4, 124·8 ± 50·0, 130·0 ± 38·3 and 189·0 ± 82·1 μg/L, respectively). C_max for the Koreans were significantly greater, compared with Hans and Mongolians. The time to attain C_max (t_max) for Hans was significantly longer as compared with Koreans and Uygurs (1·5 ± 0·7, 0·8 ± 0·5, 0·6 ± 0·7 h, respectively). Midazolam terminal half‐life (t_1/2z) were 3·0 ± 0·8, 2·2 ± 0·7, 1·9 ± 0·7, 3·5 ± 1·9, 3·8 ± 2·3 h for Hans, Mongolians, Uygurs, Huis and Koreans, respectively. The differences in half‐life were significant between Koreans and Mongolians, Koreans and Uygurs, Uygurs and Huis, respectively. There were no differences between young males and females for all pharmacokinetic parameters. Double peaks in the concentration–time profiles were observed in some subjects. What is new and Conclusion: There were some significant differences in midazolam pharmacokinetics between the five Chinese ethnic groups. However, the wide intra‐ethnic variability observed in PK parameters makes predictions of midazolam kinetics, using ethnicity as predictor, unreliable.