摘要:

The use of proton pump inhibitors (PPIs) has become widespread in children and infants for the management of paediatric acid-related disease. Pharmacokinetic profiles of only omeprazole and lansoprazole have been well characterised in children over 2 years of age with acid-related diseases. Few data have been recently published regarding the pharmacokinetics of pantoprazole in children, and none are available for rabeprazole or esomeprazole. The metabolism of PPI enantiomers has never been studied in the paediatric population.A one-compartment model best describes the pharmacokinetic behaviour of omeprazole, lansoprazole and pantoprazole in children, with important interindividual variability for each pharmacokinetic parameter. Like adults, PPIs are rapidly absorbed in children following oral administration; the mean time to reach maximum plasma concentration varies from 1 to 3 hours. Since these agents are acid labile, their oral formulations consist of capsules containing enteric-coated granules. No liquid formulation is available for any of the PPIs. Thus, for those patients unable to swallow capsules, extemporaneous liquid preparations for omeprazole and lansoprazole have been reported; however, neither the absolute nor the relative bioavailabilities of these oral formulations have been studied in children. Intravenous formulations are available for omeprazole (in Europe), lansoprazole and pantoprazole.PPIs are rapidly metabolised in children, with short elimination half-lives of around 1 hour, similar to that reported for adults. All PPIs are extensively metabolised by the liver, primarily by cytochrome P450 (CYP) isoforms CYP2C19 and CYP3A4, to inactive metabolites, with little unchanged drug excreted in the urine. Similar to that seen in adults, the absolute bioavailability of omeprazole increases with repeated dosing in children; this phenomenon is thought to be due to a combination of decreased first-pass elimination and reduced systemic clearance. The apparent clearance (CL/F) of omeprazole, lansoprazole and pantoprazole appears to be faster for children than for adults. A higher metabolic capacity in children as well as differences in the extent of PPI bioavailability are most likely responsible for this finding. This may partly account for the need in children for variable and sometimes considerably greater doses of PPIs, on a per kilogram basis, than for adults to achieve similar plasma concentrations. Furthermore, no studies have been able to demonstrate a statistically significant correlation between age and pharmacokinetic parameters among children. Despite the small number of very young infants studied, there is some evidence for reduced PPI metabolism in newborns. The limited paediatric data regarding the impact of CYP2C19 genetic polymorphism on PPI metabolism are similar to those reported for adults, with poor metabolisers having 6- to 10-fold higher area under the concentration-time curve values compared with extensive metabolisers.Finally, because a pharmacokinetic/pharmacodynamic relationship exists for PPIs, the significant interindividual variability in their disposition may partly explain the wide range of therapeutic doses used in children. Further studies are needed to better define the pharmacokinetics of PPIs in children <2 years of age.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Following oral administration, ezetimibe is rapidly absorbed and extensively metabolised (>80%) to the pharmacologically active ezetimibe-glucuronide. Total ezetimibe (sum of ‘parent’ ezetimibe plus ezetimibe-glucuronide) concentrations reach a maximum 1-2 hours post-administration, followed by enterohepatic recycling and slow elimination. The estimated terminal half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours. Consistent with the elimination half-life of ezetimibe, an approximate 2-fold accumulation is observed upon repeated once-daily administration.The recommended dose of ezetimibe 10 mg/day can be administered in the morning or evening without regard to food. There are no clinically significant effects of age, sex or race on ezetimibe pharmacokinetics and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. The major metabolic pathway for ezetimibe consists of glucuronidation of the 4-hydroxyphenyl group by uridine 5′-diphosphate-glucuronosyltransferase isoenzymes to form ezetimibe-glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the faeces predominantly as ezetimibe, with the balance found in the urine mainly as ezetimibe-glucuronide.Overall, ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between ezetimibe and a variety of drugs commonly used in patients with hypercholesterolaemia. Ezetimibe does not have significant effects on plasma levels of HMG-CoA reductase inhibitors commonly known as statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibric acid derivatives (gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and triphasic oral contraceptives (ethinylestradiol and levonorgestrel). Concomitant administration of food, antacids, cimetidine or statins had no significant effect on ezetimibe bioavailability. Although coadministration with gemfibrozil and fenofibrate increased the bioavailability of ezetimibe, the clinical significance is thought to be minor considering the relatively flat dose-response curve of ezetimibe and the lack of dose-related increase in adverse events. In contrast, coadministration with the bile acid binding agent colestyramine significantly decreased ezetimibe oral bioavailability (based on area under the plasma concentration-time curve of total ezetimibe). Hence, ezetimibe and colestyramine should be administered several hours apart to avoid attenuating the efficacy of ezetimibe. Finally, higher ezetimibe exposures were observed in patients receiving concomitant ciclosporin, and ezetimibe caused a small but statistically significant effect on plasma levels of ciclosporin. Because treatment experience in patients receiving ciclosporin is limited, physicians are advised to exercise caution when initiating ezetimibe in the setting of ciclosporin coadministration, and to carefully monitor ciclosporin levels.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

BackgroundValganciclovir (Valcyte®) has recently been approved for the prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+]/recipient negative [R–]) solid organ transplant (SOT) recipients. Large-scale studies describing the pharmacokinetics of valganciclovir in SOT recipients are  lacking.  A  recent  randomised,  double-blind  study  of  valganciclovir  in 364 D+/R– (intent-to-treat population) SOT recipients provided valuable data on which a population pharmacokinetic analysis was performed.MethodsThe pharmacokinetics of ganciclovir from oral ganciclovir (Cymevene®, 1000mg three times daily) and from valganciclovir (900mg once daily) were described with plasma levels from 240 patients (1181 datapoints describing 449 pharmacokinetic profiles) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment pharmacokinetic model with separate absorption/metabolism and absorption parameters for valganciclovir and ganciclovir, respectively, was developed.ResultsExposure to ganciclovir from valganciclovir averaged 1.65-fold greater than that from  oral  ganciclovir  (95%  CI  1.58,  1.81);  respective  daily  area under the plasma concentration-time curve values were 46.3 ± 15.2 μg · h/mL and 28.0 ± 10.9 μg · h/mL. The relative systemic exposure of ganciclovir was approximately 8-fold higher from valganciclovir than oral ganciclovir. Exposure to ganciclovir from valganciclovir was similar among liver, heart and kidney transplant recipients (46.0 ± 16.1, 40.2 ± 11.8 and 48.2 ± 14.6 μg · h/ mL, respectively). Adherence to the prescribed dosing regimens, which were reduced for renal impairment, gave consistent exposure to ganciclovir.ConclusionOral valganciclovir produces exposures of ganciclovir exceeding those attained with oral ganciclovir, but in line with those reported after standard intravenous administration of ganciclovir. This indicates that oral valganciclovir is suitable in circumstances requiring prophylactic use of ganciclovir and allows for more convenient management of patients at risk of CMV disease.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveCinacalcet (cinacalcet HCl; Sensipar®/Mimpara®) is a calcimimetic that is a treatment for secondary hyperparathyroidism in patients with renal failure. The objective of this study was to assess the effects of renal function and dialysis on the pharmacokinetics and pharmacodynamics of cinacalcet.MethodsTwo open-label, single-dose (75mg) studies of cinacalcet were performed: study 1 examined 36 subjects who had renal function ranging from normal to requiring haemodialysis, and study 2 examined ten subjects who were receiving continuous ambulatory peritoneal dialysis. Cinacalcet plasma concentrations were determined using a liquid chromatography-mass spectrometry/mass spectrometry assay. Cinacalcet pharmacokinetics were assessed using noncompartmental analyses.ResultsFollowing single-dose administration of cinacalcet, there was no evidence of increasing exposure with increasing degree of renal impairment, and the pharmacokinetic profile was similar for all subjects regardless of whether they were receiving haemodialysis (no difference on dialysis or nondialysis days detected) or peritoneal dialysis. Protein binding of cinacalcet, determined in study 1 only, was similar in all groups and the level of renal function did not affect the pharmacodynamics (as determined by intact parathyroid hormone and calcium levels). No serious adverse events occurred during either study.ConclusionThe degree of renal impairment and mode of dialysis do not affect the pharmacokinetics or pharmacodynamics of cinacalcet. Therefore, the dose of cinacalcet does not need to be altered for degree of renal impairment or dialysis modality.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectivesThis study evaluated the effect of the addition of zonisamide on valproic acid (valproate sodium) pharmacokinetics under steady-state conditions in patients with epilepsy. A second aim was to characterise zonisamide pharmacokinetics in the presence of valproic acid.MethodsTwenty-two patients (males and females, 18–55 years of age) with their seizure disorder stabilised on valproic acid monotherapy were included in a two-centre, open-label, one-way drug-interaction trial. The zonisamide dose was gradually increased from 100 mg/day to 400 mg/day. Three pharmacokinetic profiles were obtained: on days −7 and −1, to assess pharmacokinetic parameters of oral valproic acid administered alone, and on day 35, after 14 days of zonisamide treatment at the maximal tolerated dose, to evaluate the effect of zonisamide on valproic acid pharmacokinetics and to characterise zonisamide pharmacokinetics in the presence of valproic acid.ResultsSeventeen patients completed the study, with 16 patients contributing to the pharmacokinetic analyses. Coadministration of zonisamide and valproic acid appeared reasonably well tolerated. Steady-state dosing of zonisamide (200mg twice daily) had no statistically significant effect on the mean (± SD) maximum observed plasma concentration (Cmax) [70.8 ± 20.5 vs 69.2 ± 27.0 μg/mL], area under the plasma concentration-time curve from the time of dosing to 12 hours post-dose (AUC12) [689.3 ± 250.4 vs 661.8 ± 251.3 μg · h/mL] or other evaluated pharmacokinetic parameters for valproic acid measured before and after zonisamide administration. Furthermore, 90% confidence intervals for the ratio of the geometric means (day 35/day −1) of valproic acid pharmacokinetic exposure measures fell only slightly outside the ‘no effect’ range of 0.80–1.25. In the presence of valproic acid, mean zonisamide oral clearance (1.23 L/h) and elimination half-life (52.5 hours) are generally consistent with values reported for healthy volunteers receiving zonisamide monotherapy.ConclusionThere is no apparent clinically significant effect of steady-state dosing of zonisamide on valproic acid pharmacokinetics, and valproic acid did not appear to affect the pharmacokinetics of zonisamide, indicating that no dosage adjustment of either drug should be required when they are used in combination in patients with epilepsy.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

BackgroundThe use of mycophenolate mofetil in combination with highly active antiretroviral therapy (HAART) has been proposed in order to inhibit HIV replication. Due to the low doses involved, pharmacokinetic-pharmacodynamic monitoring is recommended.ObjectiveThe aim of this study was to characterise the pharmacokinetic and pharmacodynamic monitoring of low doses of mycophenolate mofetil (0.25g twice daily) in HIV-infected patients treated with HAART and after programmed discontinuation of HAART, in order to assess whether low doses of this immunosuppressive agent provide a biological effect.MethodsMycophenolic acid (MPA) plasma levels (assessed by high-performance liquid chromatography) and the capacity of patients’ sera to inhibit CEM cell line proliferation (assessed by3H-thymidine uptake) were measured post-dose at 0, 20, 40 minutes and 1, 2, 4, 6, 8, 10 and 12 hours in nine HIV-infected patients treated with a combination of abacavir, nelfinavir and efavirenz (HAART) and mycophenolate mofetil 0.25g twice daily at days 7, 28, 120 and 150 (30 days without HAART) after the treatment initiation. A control group of eight patients was treated with HAART alone.ResultsIn the 35 post-dose curves analysed, no differences were found in MPA levels between days 7, 28, 120 and 150: area under the plasma concentration-time curve – mean value 15.3 mg · h/L, range 10.4–24.4 mg · h/L; minimum plasma concentration – mean value 0.60 mg/L, range 0.20–4.67 mg/L; maximum plasma concentration mean value 2.60 mg/L, range 0.94–7.98 mg/L. Pretreatment patients’ sera did not inhibit CEM proliferation. Post-treatment patients’ sera inhibited CEM proliferation to <40% in 25 of 35 curves at 0 hours (six of nine patients), in 34 of 35 curves at 1 hour, in 32 of 35 curves at 2 hours, in 22 of 35 curves at 4 hours, and in 8 of 35 curves at 12 hours. The MPA level versus CEM proliferation inhibition had a concentration that produces 50% of the maximum drug effect (EC50) of 0.33 mg/L. Viral load at day 150 was >200 copies/mL in all control patients and in three of nine patients receiving mycophenolate mofetil. These three patients were the only ones repeatedly unable to inhibit pre-dose CEM proliferation to <40%.ConclusionsMycophenolate mofetil pharmacokinetic profiles in HIV patients under HAART are not significantly different from those found in transplant patients. Sera from the majority of patients receiving low doses of mycophenolate mofetil inhibited lymphocyte proliferation during most of the inter-dose interval, despite low MPA plasma levels. For some patients, higher doses may be necessary: the capacity of sera to inhibit CEM proliferation may help to identify these patients.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveTo evaluate and compare the pharmacokinetic profiles of imipenem and meropenem in a population of critically ill patients with sepsis to find possible differences that may help in selecting the most appropriate drug and/or dosage in order to optimise empiric antimicrobial therapy.Patients and methodsThis was a single-centre, randomised, nonblind study of the pharmacokinetics of both intravenous imipenem 1g and meropenem 1g in 20 patients admitted to an intensive care unit with sepsis in whom antimicrobial therapy was indicated on clinical grounds. Patients were divided into two groups: group I received intravenous imipenem 1g plus cilastatin 1g, and group II received intravenous meropenem 1g over 30 minutes. Peripheral blood samples were collected at 0, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hours after the first dose and were centrifuged for 10 minutes at 4ºC. Urine samples were collected during the 8 hours after antimicrobial administration at 2-hour intervals: 0–2, 2–4, 4–6 and 6–8 hours. The total volume of urine was recorded; the serum and urine samples were immediately frozen and stored at −80ºC until assayed. Pharmacokinetic analysis was carried out through computerised programs using the least-square regression method and a two-compartment open model. Statistical differences were evaluated by means of one-way ANOVA.ResultsThe following pharmacokinetic differences between the two drugs were observed: the imipenem mean peak serum concentration was significantly higher than for meropenem (90.1 ± 50.9 vs 46.6 ± 14.6 mg/L, p < 0.01); the area under the serum concentration-time curve was significantly higher for imipenem than for meropenem (216.5 ± 86.3 vs 99.5 ± 23.9 mg · h/L, p < 0.01), while the mean volume of distribution and mean total clearance were significantly higher for meropenem than for imipenem (25 ± 4.1 vs 17.4 ± 4.5L, p < 0.01 and 191 ± 52.2 vs 116.4 ± 42.3 mL/min, p < 0.01, respectively).ConclusionThe more favourable pharmacokinetic profile of imipenem compared with meropenem in critically ill patients with sepsis might balance the possibly greater potency demonstratedin vitrofor meropenem against Gram-negative strains. Hence, the clinical efficacy of the two carbapenems depends mostly on their correct dosage.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS