Posaconazole-ibrutinib interaction cannot be avoided by staggered dosing: How to optimize ibrutinib dose during posaconazole treatment.

AIMS: Ibrutinib is used in the treatment of certain B-cell malignancies. Due to its CYP3A4-mediated metabolism and highly variable pharmacokinetics, it is prone to potentially harmful drug-drug interactions. METHODS: In a randomized, placebo-controlled, three-phase crossover study, we examined the effect of the CYP3A4-inhibiting antifungal posaconazole on ibrutinib pharmacokinetics. Eleven healthy participants ingested repeated doses of 300 mg of posaconazole either in the morning or in the evening, or placebo. A single dose of ibrutinib (30, 70 or 140 mg, respectively) was administered at 9 AM, 1 or 12 h after the preceding posaconazole/placebo dose. RESULTS: On average, morning posaconazole increased the dose-adjusted geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0-∞ ) and peak plasma concentration (Cmax ) of ibrutinib 9.5-fold (90% confidence interval [CI] 6.3-14.3, P < 0.001) and 8.5-fold (90% CI 5.7-12.8, P < 0.001), respectively, while evening posaconazole increased those 10.3-fold (90% CI 6.7-16.0, P < 0.001) and 8.2-fold (90% CI 5.2-13.2, P < 0.001), respectively. Posaconazole had no significant effect on the half-life of ibrutinib, but substantially reduced the metabolite PCI-45227 to ibrutinib AUC0-∞ ratio. There were no significant differences in ibrutinib pharmacokinetics between morning and evening posaconazole phases. CONCLUSIONS: Posaconazole increases ibrutinib exposure substantially, by about 10-fold. This interaction cannot be avoided by dosing the drugs 12 h apart. In general, a 70-mg daily dose of ibrutinib should not be exceeded during posaconazole treatment to avoid potentially toxic systemic ibrutinib concentrations.

Lifetime antimicrobial use is associated with weight status in early adolescence-A register-based cohort study.

BACKGROUND: Antimicrobial agents (AMs) are the most prescribed drugs to children. Early and repeated exposure to AMs in infancy is associated with increased risk of childhood overweight and obesity. AIMS: We extended the investigation of AMs use, from birth to early adolescence, and evaluated their association with weight status. MATERIALS & METHODS: A total of 10093 children from Finnish Health in Teens cohort (Fin-HIT) with register-based data on AMs purchases and measured weight status at the mean age of 11.2 y (SD 0.82) were included in the study. The key exposures were the number AM purchases at a given age or the sum of these during the entire follow-up time to describe lifetime exposure / use. Outcome was weight status in early adolescence defined with International Obesity Task Force cut-offs for the age- and sex-specific body mass index. Odds Ratio (OR) and 95% confidence intervals (CI) were estimated using Multinomial Logistic Regression. RESULTS: Of children, 73.7% were normal weight, 11.1% thin and 15.2% overweight/obese. AMs use was highest during the second year of life, when 65% of all children used AMs, but thereafter decreased with age. The highest mean purchases and prevalence at any given age along with the highest lifetime use were consistently seen among overweight children. Each episode of AMs use throughout life increased the risk of being overweight in adolescence [OR = 1.02 (1.02-1.03)]. However, there was an inverse association between AMs use and thinness [OR = 0.98 (0.97-0.99)]. DISCUSSION: Despite a high prevalence of AMs use during the early years, lifetime-use was associated with weight status in early adolescence in a dose response manner. CONCLUSION: Future studies should address mechanisms underlying the relationship between AM use and weight.

Antimicrobial drug use in the first decade of life influences saliva microbiota diversity and composition.

BACKGROUND: The human microbiota contributes to health and well-being. Antimicrobials (AM) have an immediate effect on microbial diversity and composition in the gut, but next to nothing is known about their long-term contribution to saliva microbiota. Our objectives were to investigate the long-term impact of AM use on saliva microbiota diversity and composition in preadolescents. We compared the lifetime effects by gender and AMs. We used data from 808 randomly selected children in the Finnish Health In Teens (Fin-HIT) cohort with register-based data on AM purchases from the Social Insurance Institution of Finland. Saliva microbiota was assessed with 16S rRNA (V3-V4) sequencing. The sequences were aligned to the SILVA ribosomal RNA database and classified and counted using the mothur pipeline. Associations between AM use and alpha-diversity (Shannon index) were identified with linear regression, while associations between beta-diversity (Bray-Curtis dissimilarity) and low, medium or high AM use were identified with PERMANOVA. RESULTS: Of the children, 53.6% were girls and their mean age was 11.7 (0.4) years. On average, the children had 7.4 (ranging from 0 to 41) AM prescriptions during their lifespan. The four most commonly used AMs were amoxicillin (n = 2622, 43.7%), azithromycin (n = 1495, 24.9%), amoxicillin-clavulanate (n = 1123, 18.7%) and phenoxymethylpenicillin (n = 408, 6.8%). A linear inverse association was observed between the use of azithromycin and Shannon index (b - 0.015, p value = 0.002) in all children, the effect was driven by girls (b - 0.032, p value = 0.001), while not present in boys. Dissimilarities were marked between high, medium and low users of all AMs combined, in azithromycin users specifically, and in boys with amoxicillin use. Amoxicillin and amoxicillin-clavulanate use was associated with the largest decrease in abundance of Rikenellaceae. AM use in general and phenoxymethylpenicillin specifically were associated with a decrease of Paludibacter and pathways related to amino acid degradations differed in proportion between high and low AM users. CONCLUSIONS: A systematic approach utilising reliable registry data on lifetime use of AMs demonstrated long-term effects on saliva microbiota diversity and composition. These effects are gender- and AM-dependent. We found that frequent lifelong use of AMs shifts bacterial profiles years later, which might have unforeseen health impacts in the future. Our findings emphasise a concern for high azithromycin use, which substantially decreases bacterial diversity and affects composition as well. Further studies are needed to determine the clinical implications of our findings. Video Abstract.

A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug-Drug Interactions.

BACKGROUND: Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. OBJECTIVE: This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail. METHODS: In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim®. The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (Cmax), and trough concentrations for multiple dosings (Ctrough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens. RESULTS: The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregate Cmax ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregate Cmax ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to < 5-6 mg/L for Ctrough, while 400 mg twice daily might be more suitable for rapid metabolizers (RMs; *1/*17, *17/*17) and normal metabolizers (NMs; *1/*1). When the model was integrated with independently developed CYP3A4 substrate models (midazolam and alfentanil), the observed AUC change of substrates by voriconazole was inside the 90% confidence interval of the predicted AUC change, indicating that CYP3A4 inhibition was appropriately incorporated into the voriconazole model. CONCLUSIONS: Both the in vitro assay and model-based simulations support TDI of CYP3A4 by voriconazole as a pivotal characteristic of this drug's PK. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management. The applicability of modeling results for patients remains to be confirmed in future studies.

Itraconazole Increases Ibrutinib Exposure 10-Fold and Reduces Interindividual Variation-A Potentially Beneficial Drug-Drug Interaction.

The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first-pass metabolism by cytochrome P450 (CYP) 3A4. The unpredictable exposure can compromise its safe and effective dosing. We examined the impact of itraconazole on ibrutinib pharmacokinetics. In a randomized crossover study, 11 healthy subjects were administered itraconazole 200 mg or placebo twice on day 1, and once on days 2-4. On day 3, 1 hour after itraconazole (placebo) and breakfast, ibrutinib (140 mg during placebo; 15 mg during itraconazole) was administered. Itraconazole increased the dose-adjusted geometric mean area under the concentration-time curve from zero to infinity (AUC0-∞ ) of ibrutinib 10.0-fold (90% confidence interval (CI) 7.2-13.9; P < 0.001) and peak plasma concentration (Cmax ) 8.8-fold (90% CI 6.3-12.1; P < 0.001). During itraconazole, the intersubject variation for the AUC0-∞ (55%) and Cmax (53%) was around half of that during placebo (104%; 99%). In conclusion, itraconazole markedly increases ibrutinib bioavailability and decreases its interindividual variability, offering a possibility to improved dosing accuracy and cost savings.

Clopidogrel and Gemfibrozil Strongly Inhibit the CYP2C8-Dependent Formation of 3-Hydroxydesloratadine and Increase Desloratadine Exposure In Humans.

A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, an H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabolites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically. We conducted a randomized crossover study in 11 healthy subjects to characterize the involvement of CYP2C8 in desloratadine metabolism and to compare the CYP2C8 inhibitory strength of clopidogrel (300 and 75 mg on two following days) with that of gemfibrozil (600 mg BID for 5 days). Compared with placebo (control), clopidogrel increased the area under the plasma concentration-time curve (AUC0-∞) and peak plasma concentration (C max) of desloratadine to 280% (P = 3 × 10-7) and 165% (P = 0.0006), respectively. The corresponding increases by gemfibrozil were to 462% (P = 4 × 10-7) and 174% (P = 0.0006). Compared with placebo, clopidogrel and gemfibrozil decreased 3-hydroxyloratadine AUC0-71h to 52% (P = 5 × 10-5) and 6% (P = 2 × 10-8), respectively. Moreover, the 3-hydroxydesloratadine:desloratadine AUC0-71 h ratios were 21% (P = 7 × 10-10) and 1.7% (P = 8 × 10-11) of control during the clopidogrel and gemfibrozil phases. Our results confirm that CYP2C8 plays a critical role in the formation of 3-hydroxydesloratadine in humans, making desloratadine a potential CYP2C8 probe substrate. Furthermore, the findings corroborate the previous estimates that clinically relevant doses of clopidogrel cause strong CYP2C8 inhibition, whereas those of gemfibrozil almost completely inactivate the enzyme in humans.

Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel.

Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC0-∞ of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8·10-7 ), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC0-∞ 3.9-fold; range 2.1-7.9-fold (P = 2·10-6 ), compared with ritonavir alone. Ritonavir decreased the AUC0-4h of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.

CYP3A4*22 Impairs the Elimination of Ticagrelor, But Has No Significant Effect on the Bioactivation of Clopidogrel or Prasugrel.

CYP3A enzymes participate in the elimination of ticagrelor and the bioactivation of clopidogrel and prasugrel. We studied the effects of functional CYP3A genetic variants (CYP3A4*22; rs35599367 and CYP3A5*3; rs776746) on the pharmacokinetics and pharmacodynamics of ticagrelor, clopidogrel, and prasugrel. Six healthy volunteers with the CYP3A4*1/*22 and CYP3A5*3/*3 genotype (CYP3A4*22 carriers), eight with the CYP3A4*1/*1 and CYP3A5*1/*3 genotype (CYP3A5 expressors), and 11-13 with the CYP3A4*1/*1 and CYP3A5*3/*3 genotypes (controls) ingested single doses of ticagrelor, clopidogrel, and prasugrel on separate occasions. Ticagrelor area under the plasma concentration-time curve (AUC) was 89% (P = 0.004) higher in CYP3A4*22 carriers than in controls. CYP3A4*22 carriers also showed more pronounced platelet inhibition at 24 hours after ticagrelor ingestion than the controls (43% vs. 21%; P = 0.029). The CYP3A5 genotype did not affect ticagrelor pharmacokinetics. Neither CYP3A5 nor CYP3A4 genotypes significantly affected prasugrel or clopidogrel. In conclusion, the CYP3A4*22 allele markedly impairs ticagrelor elimination enhancing its antiplatelet effect.

Withdrawal from long-term use of zopiclone, zolpidem and temazepam may improve perceived sleep and quality of life in older adults with primary insomnia.

Long-term use of benzodiazepines or benzodiazepine receptor agonists is widespread, although guidelines recommend short-term use. Only few controlled studies have characterized the effect of discontinuation of their chronic use on sleep and quality of life. We studied perceived sleep and quality of life in 92 older (age 55-91 years) outpatients with primary insomnia before and after withdrawal from long-term use of zopiclone, zolpidem or temazepam (BZDA). BZDA was withdrawn during 1 month, during which the participants received psychosocial support and blindly melatonin or placebo. A questionnaire was used to study perceived sleep and quality of life before withdrawal, and 1 month and 6 months later. 89 participants completed the 6-month follow-up. As melatonin did not improve withdrawal, all participants were pooled and then separated based solely on the withdrawal results at 6 months (34 Withdrawers. 55 Nonwithdrawers) for this secondary analysis. At 6 months, the Withdrawers had significantly (P < 0.05) shorter sleep-onset latency and less difficulty in initiating sleep than at baseline and when compared to Nonwithdrawers. Compared to baseline, both Withdrawers and Nonwithdrawers had at 6 months significantly (P < 0.05) less fatigue during the morning and daytime. Stress was alleviated more in Withdrawers than in Nonwithdrawers (P < 0.05). Satisfaction with life and expected health 1 year later improved (P < 0.05) in Withdrawers. In conclusion, sleep disturbances, daytime fatigue and impaired quality of life may resolve within 6 months of BZDA withdrawal. These results encourage withdrawal from chronic use of benzodiazepine-type hypnotics, particularly in older subjects.

Voriconazole greatly increases the exposure to oral buprenorphine.

PURPOSE: Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine. METHODS: Twelve healthy volunteers were given either placebo or voriconazole (orally, 400 mg twice on day 1 and 200 mg twice on days 2-5) for 5 days in a randomized, cross-over study. On day 5, they ingested 0.2 mg (3.6 mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0 mg. RESULTS: Voriconazole greatly increased the mean area under the plasma concentration-time curve (AUC0-18) of buprenorphine (4.3-fold, P < 0.001), its peak concentration (Cmax) (3.9-fold), half-life (P < 0.05), and excretion into urine (Ae; P < 0.001). Voriconazole also markedly enhanced the Cmax (P < 0.001), AUC0-18 (P < 0.001), and Ae (P < 0.05) of unconjugated norbuprenorphine but decreased its renal clearance (P < 0.001). Mild dizziness and nausea occurred during both study phases. CONCLUSIONS: Voriconazole greatly increases exposure to oral buprenorphine, mainly by inhibiting intestinal and liver CYP3A4. Effect on some transporters may explain elevated norbuprenorphine concentrations. Although oral buprenorphine is not commonly used, this interaction may become relevant in patients receiving sublingual buprenorphine together with voriconazole or other CYP3A4 or transporter inhibitors.

Semimechanistic Population Pharmacokinetic Model to Predict the Drug-Drug Interaction Between S-ketamine and Ticlopidine in Healthy Human Volunteers.

Low-dose oral S-ketamine is increasingly used in chronic pain therapy, but extensive cytochrome P450 (CYP) mediated metabolism makes it prone to pharmacokinetic drug-drug interactions (DDIs). In our study, concentration-time data from five studies were used to develop a semimechanistic model that describes the ticlopidine-mediated inhibition of S-ketamine biotransformation. A mechanistic model was implemented to account for reversible and time-dependent hepatic CYP2B6 inactivation by ticlopidine, which causes elevated S-ketamine exposure in vivo. A pharmacokinetic model was developed with gut wall and hepatic clearances for S-ketamine, its primary metabolite norketamine, and ticlopidine. Nonlinear mixed effects modeling approach was used (NONMEM version 7.3.0), and the final model was evaluated with visual predictive checks and the sampling-importance-resampling procedure. Our final model produces biologically plausible output and demonstrates that ticlopidine is a strong inhibitor of CYP2B6 mediated S-ketamine metabolism. Simulations from our model may be used to evaluate chronic pain therapy with S-ketamine.

Long-term persistence of withdrawal of temazepam, zopiclone, and zolpidem in older adults: a 3-year follow-up study.

BACKGROUND: Studies on persistence of benzodiazepine agonist (BZDA) withdrawal in older outpatients are few, and few studies on long-term persistence over years have yet been published. To describe the persistence of temazepam, zolpidem, and zopiclone (BZDA) withdrawal among older outpatients at 3 years from the beginning of withdrawal, as well as any changes in use of other medications. METHODS: 92 outpatients (≥55 years) with primary insomnia, long-term BZDA use as hypnotics (mean duration of BZDA use 9.9 ± 6.2 years), and willingness to withdraw from BZDAs each received either melatonin or a placebo nightly for one month. During this period, BZDAs were meant to be gradually withdrawn. Sleep hygiene counselling and psychosocial support were provided. Three years later, use of BZDAs and other medications was determined by interview and confirmed from medical records. RESULTS: Of the original 92 outpatients, 83 (90%) participated in the 3-year survey (mean follow-up 3.3 ± 0.2 years). The number of BZDA-free participants decreased from 34 (37%) at 6 months to 26 (28%; intention-to-treat) at 3 years, that of irregular BZDA users decreased from 44 (48%) at 6 months to 27 (29%) at 3 years, while that of regular users increased from 11 (12%) at 6 months to 30 (33%) at 3 years (P = 0.001). Those who were regular BZDA users at 3 years had at baseline (before withdrawal) higher BMI (P = 0.001) than did other participants. At 3 years, the total number of medications remained unchanged for non-users (P = 0.432), but increased for the irregular (P = 0.011) and regular users (P = 0.026) compared to baseline. At 3 years, compared to baseline, use of antidepressants, dopamine agonists, melatonin, and NSAIDs/paracetamol was significantly more common in the whole cohort, but their use did not differ between the BZDA-user subgroups. Randomization to melatonin or placebo during BZDA withdrawal was unrelated to BZDA-withdrawal result. CONCLUSIONS: At 3 years after withdrawal, the number of BZDA-free participants had decreased, but still one-third of the subjects remained BZDA-free, and one-third had reduced their use. Successful BZDA withdrawal did not lead to any increase in total number of medications; use of symptomatic medications in the whole cohort, however, did increase.

Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects.

Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on CES1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n = 106) and pharmacodynamics (n = 46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel. Using massively parallel sequencing, we discovered two CES1 SNVs, rs12443580 and rs8192935, to be strongly and independently associated with a 39% (p = 4.0 × 10-13 ) and 31% (p = 2.5 × 10-8 ) reduction in CES1 whole blood expression per copy of the minor allele. These findings were replicated in the replication cohort. However, these SNVs did not affect CES1 liver expression, or clopidogrel pharmacokinetics or pharmacodynamics. Conversely, the CES1 c.428G>A missense SNV (rs71647871) impaired the hydrolysis of clopidogrel, increased exposure to clopidogrel active metabolite and enhanced its antiplatelet effects. In conclusion, the rs12443580 and rs8192935 variants reduce CES1 expression in whole blood but not in the liver. These tissue-specific effects may result in substrate-dependent effects of the two SNVs on CES1-mediated drug metabolism.

Clopidogrel but Not Prasugrel Significantly Inhibits the CYP2C8-Mediated Metabolism of Montelukast in Humans.

The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y12 inhibitors on montelukast pharmacokinetics. Clopidogrel (300 mg on day 1 and 75 mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P < 0.001) and decreased the M6:montelukast AUC0-7h ratio to 45% of control (90% CI 40-50%, P < 0.001). Prasugrel (60 mg on day 1 and 10 mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.

Clopidogrel Carboxylic Acid Glucuronidation is Mediated Mainly by UGT2B7, UGT2B4, and UGT2B17: Implications for Pharmacogenetics and Drug-Drug Interactions .

The antiplatelet drug clopidogrel is metabolized to an acyl-ß-d-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl-ß-d-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLMs and HIMs, respectively) and selected human recombinant UGTs based on preliminary screening. The effects of relevant UGT polymorphisms on the pharmacokinetics of clopidogrel were evaluated in 106 healthy volunteers. UGT2B7 and UGT2B17 exhibited the greatest level of clopidogrel carboxylic acid glucuronidation activities, with a CLint,u of 2.42 and 2.82 µl⋅min-1⋅mg-1, respectively. Of other enzymes displaying activity (UGT1A3, UGT1A9, UGT1A10-H, and UGT2B4), UGT2B4 (CLint,u 0.51 µl⋅min-1⋅mg-1) was estimated to contribute significantly to the hepatic clearance. Nonselective UGT2B inhibitors strongly inhibited clopidogrel acyl-ß-d-glucuronide formation in HLMs and HIMs. The UGT2B17 inhibitor imatinib and the UGT2B7 and UGT1A9 inhibitor mefenamic acid inhibited clopidogrel carboxylic acid glucuronidation in HIMs and HLMs, respectively. Incubation of clopidogrel carboxylic acid in HLMs with UDPGA and NADPH resulted in strong inhibition of CYP2C8 activity. In healthy volunteers, the UGT2B17*2 deletion allele was associated with a 10% decrease per copy in the plasma clopidogrel acyl-ß-d-glucuronide to clopidogrel carboxylic acid area under the plasma concentration-time curve from 0 to 4 hours (AUC0-4) ratio (P < 0.05). To conclude, clopidogrel carboxylic acid is metabolized mainly by UGT2B7 and UGT2B4 in the liver and by UGT2B17 in the small intestinal wall. The formation of clopidogrel acyl-ß-d-glucuronide is impaired in carriers of the UGT2B17 deletion. These findings may have implications regarding the intracellular mechanisms leading to CYP2C8 inactivation by clopidogrel.

Analgesic Plasma Concentrations of Oxycodone After Surgery for Breast Cancer-Which Factors Matter?

We investigated factors affecting analgesic oxycodone concentrations after breast cancer surgery in 1,000 women. Preoperatively, we studied heat and cold pain sensitivities and anxiety scores. Postoperatively, rest and motion pain intensities were measured and intravenous oxycodone was administered until satisfactory analgesia. At this point, the mean oxycodone concentration (variation coefficient) was 33.3 ng/mL (66%) and it was 21.7 ng/mL (69%) when the patient requested oxycodone again. At both time points, the concentrations varied >100-fold between individuals. The analgesic oxycodone concentration was increased by 21.3% per motion pain intensity score on a 0-10 scale and by 22.3% if axillary clearance was performed instead of sentinel node biopsy (P < 0.001). Forty-seven women who were older and less anxious than others (P < 0.01) required no oxycodone. Anxiety, age, chronic pain, or preoperative pain sensitivity were not independently associated with the analgesic oxycodone concentration. CYP2D6 and CYP3A genotypes did not affect analgesic concentration or duration of analgesia.

Stress-Dose Corticosteroid Versus Placebo in Neonatal Cardiac Operations: A Randomized Controlled Trial.

BACKGROUND: Corticosteroids can improve the hemodynamic status of neonates with postoperative low cardiac output syndrome after cardiac operations. This study compared a prophylactically administered stress-dose corticosteroid (SDC) regimen against placebo on inflammation, adrenocortical function, and hemodynamic outcome. METHODS: Forty neonates undergoing elective open heart operations were randomized into two groups. The SDC group received perioperatively 2 mg/kg methylprednisolone, and 6 hours after the operation, a hydrocortisone infusion (0.2 mg/kg/h) was started with tapering doses for 5 days. Placebo was administered in a similar fashion. An adrenocorticotropic hormone stimulation test was performed after the therapy. The primary endpoint of the study was plasma concentration of interleukin (IL-6). Secondary clinical outcomes included plasma cortisol, IL-10, C-reactive protein, echocardiographic systemic ventricle contractility evaluated by the Velocity Vector Imaging program, the inotropic score, and time of delayed sternal closure. RESULTS: The IL-6 values of the SDC group were significantly lower postoperatively than in the placebo group. Significantly lower inotropic scores (p < 0.05), earlier sternal closure (p = 0.03), and less deterioration in the systemic ventricle mean delta strain values between the preoperative and the first postoperative assessment (p = 0.01) were detected for the SDC group. The SDC therapy did not suppress the hypothalamic-pituitary-adrenal axis more than placebo. The mean plasma cortisol level did not decline in the placebo group after the operation. CONCLUSIONS: The SDC regimen for 5 days postoperatively in neonates was safe and did not cause suppression of the hypothalamic-pituitary-adrenal axis. Furthermore, the open heart operation per se did not lead to adrenal insufficiency in neonates.

Role of gemfibrozil as an inhibitor of CYP2C8 and membrane transporters.

INTRODUCTION: Cytochrome P450 (CYP) 2C8 is a drug metabolizing enzyme of major importance. The lipid-lowering drug gemfibrozil has been identified as a strong inhibitor of CYP2C8 in vivo. This effect is due to mechanism-based inhibition of CYP2C8 by gemfibrozil 1-O-ß-glucuronide. In vivo, gemfibrozil is a fairly selective CYP2C8 inhibitor, which lacks significant inhibitory effect on other CYP enzymes. Gemfibrozil can, however, have a smaller but clinically meaningful inhibitory effect on membrane transporters, such as organic anion transporting polypeptide 1B1 and organic anion transporter 3. Areas covered: This review describes the inhibitory effects of gemfibrozil on CYP enzymes and membrane transporters. The clinical drug interactions caused by gemfibrozil and the different mechanisms contributing to the interactions are reviewed in detail. Expert opinion: Gemfibrozil is a useful probe inhibitor of CYP2C8 in vivo, but its effect on membrane transporters has to be taken into account in study design and interpretation. Moreover, gemfibrozil could be used to boost the pharmacokinetics of CYP2C8 substrate drugs. Identification of gemfibrozil 1-O-ß-glucuronide as a potent mechanism-based inhibitor of CYP2C8 has led to recognition of glucuronide metabolites as perpetrators of drug-drug interactions. Recently, also acyl glucuronide metabolites of clopidogrel and deleobuvir have been shown to strongly inhibit CYP2C8.