Effect of omeprazole on the pharmacokinetics of paricalcitol in healthy subjects
Department of Clinical Pharmacology and Pharmacometrics, Abbott, Abbott Park, IL 60064, USA.Biopharmaceutics & Drug Disposition (Impact Factor: 2.34). 03/2007; 28(2):65-71. DOI: 10.1002/bdd.532
Paricalcitol capsules are indicated for the prevention and treatment of secondary hyperparathyroidism in chronic kidney disease (CKD). Proton pump inhibitors are prescribed to CKD patients to treat gastroesophageal reflux. This was a single dose, crossover study evaluating the effect of omeprazole, change in gastric pH as a result thereof, on the pharmacokinetics (PK) of paricalcitol. Twenty-six healthy subjects were administered paricalcitol capsules (16 microg) alone (regimen A), and following a single dose of OMP (40 mg) (regimen B), with a washout of at least 7 days. Plasma samples for paricalcitol concentrations were collected for 48 h post-paricalcitol dose. The plasma paricalcitol concentrations were measured using an LC-MS/MS assay (LOQ=0.02 ng/ml) and paricalcitol pharmacokinetic parameters were estimated using non-compartmental methods. The point estimates and the corresponding 90% confidence intervals for Cmax and AUC0-infinity to evaluate paricalcitol-omeprazole interaction were 1.032 [0.920-1.158] and 1.041 [0.951-1.139], respectively. No significant differences in Tmax (regimen A: 2.9 h vs regimen B: 2.6 h) or t1/2 (6.83 h vs 6.6 h) between the regimens were observed. Hence, the co-administration of omeprazole does not affect the PK of paricalcitol. Both regimens were well tolerated and no apparent differences among the regimens with respect to safety were observed.
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ABSTRACT: Proton pump inhibitors (PPIs) are widely prescribed for the treatment of gastric acid-related disorders and the eradication of Helicobacter pylori. In addition, they are routinely prescribed for the prevention of gastrointestinal bleeding in patients receiving a dual antiplatelet therapy consisting of clopidogrel and aspirin (acetylsalicylic acid) after myocardial infarction or percutaneous coronary intervention and stenting. Because PPIs are given to these patients for long periods, there is a concern about the potential for clinically significant drug-drug interactions (DDIs) with concomitantly administered medications. Because PPIs give rise to profound and long-lasting elevation of intragastric pH, it is not surprising that they interfere with the absorption of concurrent medications. Drug solubility may be substantially reduced at neutral pH compared with acidic conditions. In this context, PPIs have been shown to reduce the bioavailability of many clinically relevant drugs (e.g. ketoconazole, atazanavir) by 50% or more compared with the control values. Soon after the introduction of omeprazole (a prototype PPI) into the market, it was reported that omeprazole was associated with 30% and 10% reductions in systemic clearance of diazepam and phenytoin, respectively. In vitro studies demonstrating the inhibitory effects of omeprazole on the metabolism of these drugs with human liver microsomes gave a mechanistic explanation for the DDIs. Numerous subsequent studies have been performed to investigate the DDI potential of PPIs associated with the metabolic inhibition of cytochrome P450 (CYP) enzyme activities; however, most such attempts have failed to find clinically relevant results. Nevertheless, recent large-scale clinical trials have raised concerns about possible DDIs between PPIs and an antiplatelet drug, clopidogrel. It has been suggested that coadministration of PPIs with a dual antiplatelet therapy consisting of clopidogrel and aspirin may attenuate the anti-aggregation effects of those medications and augment the risk of cardiovascular ischaemic events. There is a possibility that PPIs may elicit detrimental effects by inhibiting CYP2C19-dominated metabolism of clopidogrel to its active metabolite. Further studies are urgently required to clarify the mechanism of this DDI and to explore new aspects of the DDI potential of PPIs.Clinical Pharmacokinetics 08/2010; 49(8):509-33. DOI:10.2165/11531320-000000000-00000 · 5.05 Impact Factor
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ABSTRACT: Secondary hyperparathyroidism is a characteristic feature of chronic kidney disease, which develops early in the course of chronic kidney disease, often in a progressive way. It occurs as the renal function continues to decline and is encountered following a series of biochemical abnormalities, which are responsible for initiation and maintenance of increased parathyroid hormone (PTH) secretion. Several agents are used in the management of secondary hyperparathyroidism. Paricalcitol is a new generation selective vitamin D receptor activator that lowers PTH levels by exerting a less hypercalcaemic and hyperphosphataemic effect. In addition, there is emerging evidence of the benefit of paricalcitol in preventing intravascular calcification and proteinuria.Journal of Renal Care 06/2011; 37(2):75-9. DOI:10.1111/j.1755-6686.2011.00230.x
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ABSTRACT: Paricalcitol injection and capsules are approved for the prevention and treatment of secondary hyperparathyroidism. Exposure-response analyses were performed to describe paricalcitol pharmacokinetics and the relationship to clinical responses (intact parathyroid hormone [iPTH], serum calcium, and phosphorus) following administration of paricalcitol capsules or injection to patients with chronic kidney disease (stage 5). Paricalcitol pharmacokinetics were similar following intravenous and oral administration with mean oral clearance of 1.75 L/h and bioavailability of 75.1%. Exposure-clinical response was best described by an indirect effects model where serum iPTH, calcium, and phosphorus production rates were directly affected by paricalcitol. Significant covariates in the response model included screening iPTH, calcium, and phosphorus on their corresponding synthesis rates; age on iPTH EC(50); and bone-specific alkaline phosphatase on calcium EC(50) (CRIT). This exposure-response model was used in extensive clinical trial simulations to assess alternative dose regimens for CKD stage 5 patients.The Journal of Clinical Pharmacology 09/2011; 52(8):1162-73. DOI:10.1177/0091270011412966 · 2.48 Impact Factor
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