Robert Z. Harris

Dietary effects on drug metabolism and transport.

Metabolic food-drug interactions occur when the consumption of a particular food modulates the activity of a drug-metabolising enzyme system, resulting in an alteration of the pharmacokinetics of drugs metabolised by that system. A number of these interactions have been reported. Foods that contain complex mixtures of phytochemicals, such as fruits, vegetables, herbs, spices and teas, have the greatest potential to induce or inhibit the activity of drug-metabolising enzymes, although dietary macroconstituents (i.e. total protein, fat and carbohydrate ratios, and total energy intake) can also have effects. Particularly large interactions may result from the consumption of herbal dietary supplements.Cytochrome P450 (CYP) 3A4 appears to be especially sensitive to dietary effects, as demonstrated by reports of potentially clinically important interactions involving orally administered drugs that are substrates of this enzyme. For example, interactions of grapefruit juice with cyclosporin and felodipine, St John’s wort with cyclosporin and indinavir, and red wine with cyclosporin, have the potential to require dosage adjustment to maintain drug concentrations within their therapeutic windows. The susceptibility of CYP3A4 to modulation by food constituents may be related to its high level of expression in the intestine, as well as its broad substrate specificity. Reported ethnic differences in the activity of this enzyme may be partly due to dietary factors.Food-drug interactions involving CYP1A2, CYP2E1, glucuronosyltransferases and glutathione S-transferases have also been documented, although most of these interactions are modest in magnitude and clinically relevant only for drugs that have a narrow therapeutic range. Recently, interactions involving drug transporters, including P-glycoprotein and the organic anion transporting polypeptide, have also been identified. Further research is needed to determine the scope, magnitude and clinical importance of food effects on drug metabolism and transport.

Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride.

Cinacalcet hydrochloride (cinacalcet) is a calcimimetic approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) receiving dialysis and for the treatment of hypercalcaemia in patients with parathyroid carcinoma.Following oral administration, peak plasma concentrations of cinacalcet occur within 2–6 hours. The absolute bioavailability is 20–25%, and administration of cinacalcet with low- or high-fat meals increases exposure (area under the plasma concentration-time curve from time zero to infinity [AUC∞]) 1.5- to 1.8-fold. Cinacalcet has no significant interaction with calcium carbonate or sevelamer hydrochloride, phosphate binders commonly used in the treatment of patients with CKD receiving dialysis. The terminal elimination half-life is 30–40 hours, and steady-state concentrations are achieved within 7 days. The pharmacokinetics of cinacalcet are dose proportional over the dose range of 30–180 mg.The pharmacokinetic profile of cinacalcet is not notably affected by varying degrees of renal impairment. The pharmacokinetics of cinacalcet are comparable between healthy subjects, patients with primary hyperparathyroidism and patients with secondary hyperparathyroidism with reduced renal function (including those patients with secondary hyperparathyroidism receiving dialysis). Additionally, the pharmacokinetics of cinacalcet are similar in patients with secondary hyperparathyroidism receiving haemodialysis and patients with secondary hyperparathyroidism receiving peritoneal dialysis. Mild hepatic impairment does not affect the pharmacokinetics of cinacalcet, whereas moderate or severe hepatic impairment increases the exposure (AUC∞) by approximately 2- and 4-fold, respectively. Age, sex, bodyweight and race do not notably affect the pharmacokinetics of cinacalcet.Cinacalcet is extensively metabolized by multiple hepatic cytochrome P450 (CYP) enzymes (primarily 3A4, 2D6 and 1A2) with <1% of the parent drug excreted in the urine. Dose adjustments of cinacalcet may be necessary, and parathyroid hormone (PTH) and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g. ketoconazole, erythromycin, itraconazole). Cinacalcet is a strong inhibitor of CYP2D6; therefore, dose adjustment of concomitant medications that are predominantly metabolized by CYP2D6 and have a narrow therapeutic index (e.g. flecainide, vinblastine, thioridazine and most tricyclic antidepressants) may be required. Cinacalcet does not appreciably inhibit or induce the activities of CYP3A4, 1A2, 2C9 or 2C19.An inverse relationship exists between plasma PTH and cinacalcet concentrations. PTH concentrations are greatest before dose administration when the cinacalcet concentration is lowest (24 hours after the previous day’s dose). Nadir PTH levels occur approximately 2–3 hours after dosing.

No Effect of Renal Function or Dialysis on Pharmacokinetics of Cinacalcet (Sensipar®/Mimpara®)

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.

Pharmacokinetics of Cinacalcet Hydrochloride When Administered with Ketoconazole

Background and objectiveThe calcimimetic cinacalcet hydrochloride (cinacalcet) is used for treatment of patients with chronic kidney disease with secondary hyperparathyroidism, a population that commonly receives multiple concurrent medications. Cinacalcet is eliminated primarily via oxidative metabolism mediated, in part, through cytochrome P450 (CYP) 3A4. Thus, the potential for an inhibitor of CYP3A4 to alter the pharmacokinetics of cinacalcet is of clinical importance. The objective of this study was to evaluate the pharmacokinetics of cinacalcet during treatment with a potent CYP3A4 inhibitor, ketoconazole.Subjects and methodsTwenty-four healthy subjects were enrolled in an open-label, crossover, phase I study to receive a single oral dose of cinacalcet (90mg) alone and with 7 days of ketoconazole (200mg twice daily). Blood samples for pharmacokinetics were collected for up to 72 hours postdose. Cinacalcet plasma concentration-time data were analysed by noncompartmental methods. Pharmacokinetic parameters were analysed using a crossover ANOVA model that included subjects who completed both treatment arms.ResultsTwenty subjects completed both treatment arms. The mean area under the plasma concentration-time curve of cinacalcet increased 2.3-fold (90% CI 1.92, 2.67) [range 1.15- to 7.12-fold] and the mean maximum plasma concentration increased 2.2-fold (90% CI 1.67, 2.78) [range 0.904- to 10.8-fold] when administered with ketoconazole, relative to when administered alone. The time to reach the maximum plasma concentration was not significantly affected, and the terminal elimination half-lives were similar between treatments.ConclusionsCo-administration of a potent CYP3A4 inhibitor moderately increased cinacalcet exposure in study subjects. This suggests that clinicians should monitor parathyroid hormone and calcium concentrations when a patient receiving cinacalcet initiates or discontinues therapy with a strong CYP3A4 inhibitor.

Pharmacokinetics and pharmacodynamics of cinacalcet in hepatic impairment : phase I, open-label, parallel-group, single-dose, single-centre study.

AbstractBackground and objective:The calcimimetic cinacalcet lowers blood parathyroid hormone (PTH), calcium and phosphorus levels and calcium-phosphorus product in patients with chronic kidney disease receiving dialysis. Cinacalcet is metabolized primarily through oxidative and conjugative pathways. Hepatic disease has the potential to alter cinacalcet metabolism. Thus, it is important to establish the potential for altered cinacalcet metabolism according to the level of hepatic function. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of cinacalcet in subjects with different degrees of hepatic function.Methods:This was a phase I, open-label, single-dose, parallel-group, single-centre study that included 24 subjects (six with normal hepatic function and six each with mild, moderate and severe hepatic impairment according to Child-Pugh criteria). Subjects were given a single 50 mg oral dose of cinacalcet. Blood samples were taken for pharmacokinetic (pre-dose and up to 120 hours post-dose) and pharmacodynamic (pre-dose and up to 72 hours post-dose) evaluations. Plasma concentrations of cinacalcet were determined using a validated normal phase turbo ion spray liquid chromatography-mass spectrometry/mass spectrometry assay. Serum ionized calcium levels were determined by standard biochemical measures, and PTH levels were determined using an immunometric intact PTH (iPTH) assay. The primary endpoints of the study were area under the concentration-time curve from 0 to time t (AUCt), AUC from 0 to infinity (AUC∞) and maximum plasma concentration (Cmax). Other pharmacokinetic parameters (time to Cmax [tmax], terminal half-life [t1/2β], total body clearance [CL/F] and protein binding) and the effect of cinacalcet on plasma PTH and serum calcium were secondary endpoints. Results: Total cinacalcet exposure (AUC∞) was comparable in subjects with normal hepatic function and mild hepatic impairment. In subjects with moderate and severe hepatic impairment, mean AUC∞ was 2.4- and 4.2-fold higher, respectively, than in healthy subjects. Cinacalcet t1/2β was 1.3- and 1.7-fold longer in subjects with moderate and severe hepatic impairment, respectively, compared with subjects with normal hepatic function. Mean Cmax and tmax, as well as protein binding, were similar in all groups. Consistent with the increase in cinacalcet exposure, decreases in iPTH tended to be greater and prolonged in subjects with moderate and severe hepatic impairment. In this study, cinacalcet was well tolerated.Conclusion:These data demonstrate that cinacalcet can be used without dose adjustment in patients with mild hepatic impairment. However, increased drug exposure observed in subjects with moderate to severe hepatic impairment indicates that iPTH and serum calcium levels should be monitored closely and physicians should be more cautious about dose titration in patients with moderate or severe hepatic impairment.

Drug interactions involving ethanol and alcoholic beverages

Ethanol is likely among the most widely and extensively used drugs in the world. It has also been demonstrated to alter the expression or activity of some drug-metabolizing enzymes. Thus, marked ethanol-provoked drug interactions could be of notable clinical importance. To date, relatively few clinically important interactions have been reported, involving cocaine, disulfiram and tacrolimus. Limited or modest interactions with ethanol have also been reported for drugs such as abacavir, cisapride, ‘ecstasy’ (3,4-methylenedioxymetamfetamine), γ-hydroxybutyrate, methylyphenidate, metronidazole and verapamil. Most of these interactions do not seem to involve CYP2E1, the enzyme initially characterized and cloned based on its ability to metabolize and be induced by ethanol. Important work has elucidated the relationship between CYP2E1-mediated formation of the hepatotoxic metabolite of acetaminophen and alcohol consumption. Lastly, drug interactions involving other components of alcoholic beverages such as flavonoid and other polyphenolic components of red wine have been reported.

The Pharmacokinetics of Cinacalcet are Unaffected Following Consumption of High- and Low-fat Meals

Cinacalcet HCl reduces iPTH, serum calcium, serum phosphorus, and the calcium-phosphorus product in patients with chronic kidney disease and secondary hyperparathyroidism who are receiving dialysis, and reduces elevated serum calcium associated with primary hyperparathyroidism and parathyroid carcinoma. Cinacalcet is administered orally, and thus concomitant administration with food may affect its bioavailability. The objective of this study was to examine the effect of fat and caloric intake on cinacalcet exposure. This phase 1, randomized, open-label, single-dose, 3-period, 3-treatment, 6-sequence crossover study enrolled 30 healthy subjects (19 men, 11 women) to receive a single oral dose of cinacalcet HCl (Sensipar®/Mimpara®; Amgen Inc. Thousand Oaks, CA) (90 mg) on 3 separate occasions: following a high-fat, high-caloric meal, a low-fat, low-caloric meal, and a 10-hour fast. Blood samples were obtained predose and up to 72 hours postdose for pharmacokinetic (AUC∞, Cmax) and safety evaluations. Twenty-nine subjects completed all the 3 treatment conditions. The mean (90% confidence intervals) AUC∞ following high- and low-fat meals was increased by 68 (48 to 89)% and 50 (33 to 70)%, respectively, relative to fasting. The difference in mean AUC∞ between high- and low-fat meals was small [12 (9.9-26)%]. The mean tmax of cinacalcet was prolonged in fasting subjects (6 h) in relation to high-fat (4 h) and low-fat (3.5 h) fed subjects. The mean t1/2β was similar between treatment conditions. Adverse events (AE) were observed at a similar frequency across the treatment conditions [high fat (34%), low fat (23%), and fasting (31%)]; the type of AE did not differ among the treatment conditions. The most common treatment-related AEs were headache 6/30 (20%), nausea 5/30 (17%), and dyspepsia 4/30 (13%) subjects. Administration of cinacalcet with either high- or low-fat meals results in significant increases in exposure, relative to administration under fasting conditions. However, the small differences observed in exposure following the ingestion of the different types of meals suggest that although food has a significant effect, the type of food does not. The observed effect supports the labeling statement that cinacalcet be taken with food, or shortly after a meal.