American Journal of Therapeutics 0, 1–10 (2015)
Effect of Omeprazole on the Pharmacokinetics of Rosuvastatin in Healthy Male Volunteers Yasar Shah, PhD,1* Zafar Iqbal, PhD,2 Lateef Ahmad, PhD,1 Fazli Khuda, MPhil,2 Abad Khan, PhD,1 Abbas Khan, PhD,1 Muhammad Imran Khan, PhD,2 and Ismail, PharmD2
The current study aimed at the evaluation of, in vivo, the effect of omeprazole on the pharmacokinetics of rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Omeprazole is an acid suppressant and CYP2C9, CYP3A4, and CYP2C19 substrate and inhibitor, as well as inhibitor of transporters (like P-gp). This was a randomized, open-label, 2-period, crossover study. Healthy male volunteers (N 5 20), divided into 2 groups, were given single oral doses of rosuvastatin 40 mg either alone (treatment period I) or concomitantly with omeprazole 40-mg capsule (treatment period II). Plasma concentrations of rosuvastatin (rosuva) and its metabolite N-desmethyl rosuvastatin (NDM-rosuva) were quantified by a validated liquid chromatography– tandem mass spectrometry method developed in our laboratory. An insignificant decrease (P . 0.05) has been observed in the values of maximum plasma concentrations, clearance, and half-life of rosuva, whereas an insignificant increase (P . 0.05) has been observed in the area under the plasma concentration–time curves from zero time to the last measurable concentration½AUCt0 , that extrapolated to infinity ½AUCN 0 , and mean residence time values after concomitant administration with omeprazole. Although omeprazole concomitant administration altered the pharmacokinetics of NDM-rosuva metabolite significantly, rosuva’s very little metabolism (10%) suggests that these changes are of no clinical significance. Concomitant administration of omeprazole with rosuva did not alter the pharmacokinetics of rosuva in healthy volunteers. These data are consistent with other reported studies, indicating that rosuva is not a good candidate for metabolism-based drug–drug interactions. Therefore, rosuva can be administered safely along with omeprazole. Keywords: rosuvastatin, pharmacokinetics, omeprazole, drug–drug interaction
INTRODUCTION Rosuvastatin (rosuva) (Figure 1) is a highly effective statin drug that strongly inhibits the 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase involved in cholesterol biosynthesis in vivo and is
1
Department of Pharmacy, University of Swabi, Swabi, Pakistan; and 2Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. The authors have no conflicts of interest to declare. *Address for correspondence: Assistant Professor, Department of Pharmacy, University of Swabi, Swabi, KPK-Pakistan. E-mail: [email protected]
used to treat hypercholesterolemia and other lipid disorders. Rosuva exerts its effects by causing reduction in the low-density lipoprotein C, total cholesterol, and triglycerides levels and elevation in the high-density lipoprotein C level.1–5 Rosuva gets its absorption from the acidic environment of the stomach and has an estimated absolute oral bioavailability of approximately 20% and absorption of 50%. It is a highly plasma protein–bound drug (88%).6 Metabolism is the minor route accounting for its elimination. Only 10% of the parent drug undergoes metabolism forming an active metabolite, that is, N-desmethyl rosuvastatin (NDM-rosuva) (Figure 1) and an inactive metabolite, that is, rosuvastatin-5Slactone (Figure 1). CYP2C9 isozyme is primarily
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Shah et al
2
FIGURE 1. Rosuva metabolism (structures of parent drug and metabolites).
involved, although CYP3A4 and CYP2C19 have little contribution in metabolism.7 About 90% of the administered dose is usually recovered in the feces unchanged.7 Rosuva absorption, hepatic uptake, and biliary and renal excretion are governed by several transporters, and recent researches have shown that transporters play a vital role in the pharmacokinetic drug–drug interaction (PK-DDI) between 2 drugs. Breast cancer resistance protein (BCRP) is an efflux transporter involved in its intestinal transport,8 whereas organic anion-transporting polypeptides (ie, OATP1B1, OATP1B3, and OATP2B1) and sodium taurocholate cotransporting polypeptide (NTCP) are involved in its hepatic uptake.8,9 Transporters involved in its biliary excretion are multidrug resistance protein 1 (MDR1), multidrug resistance associated protein 2 (MRP2), BCRP, and bile salt exporter protein,8,9 whereas renal excretion occurs through MDR1 (or P-gp).9 Omeprazole, being a prototype of proton pump inhibitors, is prescribed mostly for gastrointestinal tract disturbances, including hyperacidity and gastroesophageal reflux disease.10,11 It is basic in nature, and metabolism occurs primarily through CYP2C19 and American Journal of Therapeutics (2015) 0(0)
CYP3A4.12 It is also a strong inhibitor of these enzymes and also a substrate of drug transporters, like BCRP. CYP3A4 inhibitors also have potential of inhibiting transporters like OATP.13 Rosuva is acidic in nature with a pKa value of 4.46, and omeprazole is basic with pKa values of 7.1 and 14.7,14 and little metabolism of rosuva by the same group of enzymes, that is, CYP2C19 and CYP3A4, that are also responsible for omeprazole metabolism may account for a possible PK-DDI between them. The possibility of transporters-based interaction cannot be ruled out as well. Therefore, potential drug interaction between omeprazole and rosuva is possible and that needs to be evaluated. So far, no PK-DDI between rosuva and omeprazole in humans has been reported. The aim of the current study was to evaluate the effect of concomitant administration of omeprazole on rosuva pharmacokinetics in healthy volunteers.
SUBJECTS AND METHODS Trial population The PK-DDI between rosuva and omeprazole was assessed in normal healthy male volunteers (N 5 20). www.americantherapeutics.com
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Omeprazole-Rosuvastatin Interaction
Their mean 6 SD of age, weight, and height were 26.05 6 2.52 years (range, 22–31 years), 64.0 6 2.47 kg (range, 60–68 kg), and 65.95 6 1.79 inches (range, 63–69 inches), respectively. The local Ethical Committee of Department of Pharmacy, University of Peshawar approved the protocol before initiation. This study was conducted in accordance with the “ethical principles of the Helsinki Declaration for medical research involving human subjects” and “Good Clinical Practice Guidelines.” Being an open-label study, all the factors from dosing till sampling procedures were explained to the volunteers after which they signed a written consent. Inclusion and exclusion criteria A strict inclusion and exclusion criteria was adopted for the eligibility of volunteers in this study. The healthy status of the participants was confirmed by conducting a detailed physical examination and obtaining complete medical history. Thorough clinical examination process including different important biochemical tests like low-density lipoprotein, highdensity lipoprotein, and triglyceride profiles and electrocardiography was performed for all the participants. Other clinical tests included liver function tests, renal function tests, blood pressure, and blood glucose level. The results of all these examinations and tests were in normal ranges, indicating their good health. Subjects having any disease like coronary heart disease, chronic renal disease, diabetes mellitus, hepatic impairment, or any other systemic pathology were excluded from this study. Subjects who were obese and smokers were also excluded because these factors also contribute to the imbalance in the lipid profile. Subjects using any type of medicines and those on special diets were also excluded. Any volunteers expressing hypersensitivity to any of the drug in this particular study were also excluded. Study design It was designed as a single-dose, randomized, 2-sequence, 2-treatment period, and crossover study with 2-week washout time in between. Rosuva either alone (40 mg) or in combination with omeprazole (rosuva 40 mg + omeprazole 40 mg) was administered to the eligible volunteers (divided in 2 groups) according to the design as presented in Table 1. The details of drug products administered to the volunteers in their specified doses and dosage forms are provided in Table 2. Drug administration Volunteers were randomly distributed in 2 groups: group I and group II. The volunteers were kept abstain www.americantherapeutics.com
3 Table 1. Study design for PK-DDI study of rosuva and omeprazole in healthy human volunteers. Treatment sequences Sequence 1
2-Week washout period Sequence 2
Group I (n 5 10)
Group II (n 5 10)
Rosuvastatin alone Rosuvastatin + omeprazole (oral tablet, dose: (rosuva oral 40 mg) tablets, dose: 40 mg and omeprazole oral capsules, dose: 40 mg)
Rosuvastatin + omeprazole (rosuva oral tablets, dose: 40 mg and omeprazole oral capsules, dose: 40 mg)
Rosuvastatin alone (oral tablet, dose: 40 mg)
from not taking any medication and were advised to fast overnight to follow the standard protocol. Rosuva and omeprazole were administered to the volunteers according to the sequences described in the Table 1. In the first sequence, group I received rosuva (2 3 20 mg tabs), whereas group II received omeprazole (2 3 20 mg capsules) along with rosuva (2 3 20 mg tabs). In the second sequence, after allocating a 1-week washout period, group I received omeprazole (2 3 20 mg capsules) along with rosuva (2 3 20 mg tabs), whereas group II received rosuva (2 3 20 mg tabs) only. To maintain uniformity and standard protocol, these mentioned drugs were administered with 1 glass full of water (250 mL). The participants were not allowed to have juices or drinks other than water during the study period, and only breakfast and lunch were served 2.0 and 6.0 hours after drug administration, respectively. Blood sampling and collection of plasma Blood samples (approximately 5 mL) for the assay of rosuva and NDM-rosuva were collected in heparinized tubes just before the first intake of rosuva (either alone or in combination with omeprazole) and at intervals of 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12, and 24 hours post dose. Plasma was separated and collected by centrifugation of the noncoagulated blood samples and then stored at 280°C until analysis. While handling and performing other experimental procedures, protection from heat and excessive light was ensured. American Journal of Therapeutics (2015) 0(0)
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Shah et al
4 Table 2. Drug products utilized in PK-DDI study of rosuva and omeprazole. Product (Trade name)
Manufacturer
Batch number
Date of manufacture
Expiry date
Aurora (rosuvastatin; 20 mg/tablet) Omega (omeprazole; 20 mg/capsule)
Ferozsons Labs Pvt, Ltd, Nowshera, Pakistan Ferozsons Labs Pvt, Ltd, Nowshera, Pakistan
9E 135
March, 2013
March, 2015
9E 179
March, 2013
March, 2016
Samples analysis for determination of rosuva and NDM-rosuva Plasma samples were analyzed for rosuva and NDMrosuva by a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) developed in our laboratory. The plasma samples collected and stored at 280°C were thawed at room temperature at the time of analysis, and drugs were extracted with a simple 1-step liquid–liquid extraction procedure using acetonitrile. The lower limit of detection and lower limit of quantification for rosuva were 0.1 and 0.2 ng/mL, whereas for NDM-rosuva, these were 0.03 and 0.1 ng/mL, respectively. The analytes were efficiently separated on HiChrom C18 (150 3 3.0 mm, 3 mm; Reading, United Kingdom) column using 0.1% formic acid in acetonitrile and 0.1% formic acid in water (70:30 vol/vol) as a mobile phase and pumped at a flow rate of 300 mL/min. A high-resolution Thermo Electron Corporation LTQ-Orbitrap mass spectrometer (San Jose, CA) was used, operated in positive ion mode with the m/z ranges set for rosuva, NDM-rosuva, and atorvastatin (internal standard) as 482.1750–482.1780, 468.1590–468.1610, and 559.2595– 559.2625 (amu), respectively. The capillary temperature was 275°C, whereas the source and capillary voltages were 4.5 kV and 35 V, respectively. The auxiliary and sheath gases were 15 and 50 (arbitrary units), respectively, and the column oven temperature and sample injection volume were 25°C and 10 mL, respectively. Correlation coefficients for both rosuva and NDM-rosuva were 0.999. The average %recoveries were above 96.0% and 98.0% for rosuva and NDM-rosuva, respectively, whereas % relative standard deviation values for both analytes were less than 1%, indicating accuracy of the method. Pharmacokinetic evaluation The pharmacokinetic parameters were calculated by a noncompartmental pharmacokinetic approach using PK Solutions (version 2.0.2; Summit Research Services, Ashland, OH). The maximum plasma concentrations (Cmax) and time to reach Cmax (Tmax) were observed directly from the plasma concentration versus time profiles and measured data of rosuva and American Journal of Therapeutics (2015) 0(0)
NDM-rosuva. Linear trapezoidal rule was utilized for the calculation of area under the plasma concentration–time curves from zero time to the last measurable concentration ½AUCt0 , whereas extrapolated to infinity ½AUCN 0 was calculated using the equation: t ½AUCN 5 ðAUC 0 þ Ct Þ=ke, where Ct is the last quan0 tifiable concentration of the drug in plasma. The elimination half-life (t1/2) was then calculated as 0.693/ke. ke is the elimination rate constant determined as the slope of the terminal portion of elimination phase of plasma concentration–time curve using linear least square regression. Statistical data interpretation The pharmacokinetic data of rosuva and its metabolite NDM-rosuva obtained from this study were analyzed statistically by the SPSS software (version 16.0; SPSS, Inc, Chicago, IL). The PK parameters were expressed as mean 6 SD. Geometric mean ratios for the treatment (rosuva plus omeprazole/rosuva alone) were calculated, and 95% confidence intervals of the mean were determined. A paired t test was performed for the comparison of PK parameters between rosuva plus omeprazole and rosuva alone treatments. P , 0.05 value was considered statistically significant.
RESULTS The plasma concentrations of rosuva and NDMrosuva were determined in healthy volunteers treated either with rosuva 40-mg oral tablet alone or in combination with omeprazole 40-mg oral capsule using the developed and validated LC-MS/MS method. A typical LC-MS/MS chromatogram of real plasma sample showing peaks and ion spectras of rosuva, NDM-rosuva, and internal standard (atorvastatin) is presented in Figure 2. The plasma concentrations of rosuva and NDM-rosuva were plotted against time on both linear (normal) and semilog graph papers (presented in Figures 3, 4). A PKspecific software, that is, PK-Summit software (version 2.0.2; PK Solutions) and Microsoft Excel were used for the determination and evaluation of PK www.americantherapeutics.com
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Omeprazole-Rosuvastatin Interaction
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FIGURE 2. Representative LC-MS/MS chromatogram of a human plasma sample treated with 40 mg of rosuvastatin showing peaks and ion spectras of rosuva, NDM-rosuva, and atorvastatin (internal standard).
parameters of rosuva and NDM-rosuva. The determined PK parameters are summarized and presented in Tables 3 and 4. PK parameters of rosuvastatin After coadministration with omeprazole 40-mg capsule, an insignificant decrease (P . 0.05) in the Cmax value of rosuva was observed as compared with rosuva administration alone. The value of tmax remained the same in both the treatments, whereas the values of ½AUC24 0 (in mean 6 SD), ½AUCN (in mean 6 SD), and mean resi0 dence time (MRT) (in mean 6 SD) of rosuva increased insignificantly (P . 0.05). The volume of distribution of rosuva decreased significantly (P , 0.05), whereas clearance and t1/2-b value decreased insignificantly (P . 0.05) in volunteers treated with omeprazole along with rosuva compared with rosuva administration alone. Results are graphically presented in Figure 5. www.americantherapeutics.com
PK parameters of NDM-rosuva Peak plasma concentrations (Cmax), ½AUC24 0 , and N ½AUC0 of NDM-rosuva decreased significantly (P , 0.05), whereas Vd, clearance, and elimination half-life values increased significantly (P , 0.05) after concomitant administration of omeprazole as compared with rosuva administration alone. A slight insignificant decrease (P . 0.05) was observed in the tmax and MRT values of NDM-rosuva after concomitant administration of omeprazole with rosuva in comparison to its administration alone. The results are graphically presented in Figure 6.
DISCUSSION Extensive work has been carried out by researchers for assessing the potential of DDI between rosuva and other drugs. The impact of other drugs over the American Journal of Therapeutics (2015) 0(0)
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FIGURE 3. Plasma concentration versus time plot of rosuvastatin in healthy human volunteers (N 5 20) after administration of rosuvastatin alone (40 mg) and in combination with omeprazole (40 mg). (A) Linear graph. (B) Semilog graph.
pharmacokinetics of rosuva is well studied, taking into consideration the metabolism (although rosuva undergoes little metabolism via CYP2C9, CYP2C19, and CYP3A4) and mainly transporters. Omeprazole is primarily metabolized by CYP2C19, CYP3A4, and CYP2C9. It is also a strong inhibitor of these enzymes.15 Furthermore, omeprazole is an acid
suppressive agent and also is a basic drug in nature, whereas the metabolism of rosuva (although little) is catalyzed by CYP2C9, CYP2C19, and CYP3A4. Rosuva is acidic in nature having pKa of 4.46. These common metabolizing enzymes provided the basis for conducting and evaluating the PK-DDI studies of rosuva and omeprazole.
FIGURE 4. Plasma concentration versus time plot of NDM-rosuva in healthy human volunteers (N 5 20) after administration of rosuvastatin alone (40 mg) and in combination with omeprazole (40 mg). (A) Linear graph. (B) Semilog graph. American Journal of Therapeutics (2015) 0(0)
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Omeprazole-Rosuvastatin Interaction
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Table 3. Pharmacokinetic parameters of rosuvastatin after concomitant administration with omeprazole (40 mg) and after administration of rosuvastatin alone (40 mg).
PK parameters of rosuva Cmax (ng/mL) Tmax (h) ½AUCt0 (ng$h/mL) ½AUCN 0 (ng$h/mL) MRT (h) Vd (mL/kg) CL (mL$h21/kg) E half-life (h)
Rosuva administration alone (mean 6 SD) 28.62 3.05 202.86 209.25 5.76 20,036.54 3269.05 4.06
6 6 6 6 6 6 6 6
5.31 0.22 25.99 28.02 0.60 5570.01 741.38 0.42
Rosuva + omeprazole administration (mean 6 SD) 28.05 3.05 210.38 212.86 5.82 16,563.34 3052.75 3.81
6 6 6 6 6 6 6 6
5.00 0.22 27.50 27.57 0.30 3916.52 655.96 0.44
GMR (mean 6 SD)
90% Confidence interval
P
6 6 6 6 6 6 6 6
0.96–1.01 0.97–1.04 1.01–1.07 1.00–1.04 0.97–1.07 0.80–0.90 0.90–0.98 0.92–0.96
0.728 1.0 0.380 0.683 0.647 0.025 0.335 0.081
0.98 1.00 1.04 1.02 1.01 0.84 0.94 0.94
0.06 0.10 0.08 0.04 0.12 0.14 0.10 0.04
GMR, geometric mean ratio.
A slight but insignificant decrease in the Cmax value (2%) of rosuva was observed after concomitant administration of omeprazole 40-mg capsule with rosuva 40-mg tablet, which is practically considered to be of no clinical significance. But the Cmax value of NDM-rosuva (metabolite) decreased significantly (26%), reflecting that rosuva metabolism decreased when rosuva was administered along with omeprazole. The reason for this may be the inhibition of enzymes responsible for rosuva metabolism, that is, CYP2C19 and CYP3A4 by omeprazole, due to the fact that omeprazole is the substrate and inhibitor of these enzymes. However, as rosuva undergoes a very little total metabolism (;10%), therefore, inhibition of rosuva metabolism by concomitant administration of omeprazole is of less clinical significance. Clinically insignificant DDIs have been reported so far between rosuva and other drugs underlying the
mechanism of enzyme induction or inhibition, indicating a little potential of rosuva for metabolismbased PK-DDIs.16,17 Fluconazole (CYP2C9 and CYP219 inhibitor), erythromycin (CYP3A4 inhibitor), itraconazole (CYP3A4 inhibitor), rifampicin, and ketoconazole (CYP2C9 inducers) did not alter the PK of rosuva significantly.18,19 The slight decrease in the Cmax of rosuva may be due to the fact that omeprazole is an acid suppressant and rosuva being an acidic drug having better absorption in acidic media, concomitant administration of omeprazole along with rosuva may decrease its absorption by elevating the gastric pH and increasing the ionization of rosuva. A DDI study reported a decrease in the absorption and bioavailability of rosuva after concomitant administration of antacid preparation (aluminium hydroxide and magnesium hydroxide) and that may be due to the
Table 4. Pharmacokinetic parameters of NDM-rosuva after concomitant administration with omeprazole (40 mg) and after administration of rosuvastatin alone (40 mg).
PK parameters of NDM-rosuva
Rosuva administration alone (mean 6 SD)
Cmax (ng/mL) Tmax (h) ½AUCt0 (ng$h/mL) ½AUCN 0 (ng$h/mL) MRT (h) Vd (mL/kg) CL (mL$h21/kg) E half-life (h)
1.73 3.9 5.38 7.02 4.27 202,818.33 105,181.75 1.50
6 6 6 6 6 6 6 6
0.40 0.31 1.21 1.74 0.52 42,745.02 24,496.29 0.29
Rosuva + omeprazole GMR administration (mean 6 SD) (mean 6 SD) 2.34 4.0 8.69 9.41 4.65 106,399.22 65,279.10 1.18
6 6 6 6 6 6 6 6
0.37 0.56 0.86 0.87 0.35 22,512.92 15,427.29 0.39
0.73 0.98 0.61 0.73 0.93 1.86 1.56 1.33
6 6 6 6 6 6 6 6
0.15 0.16 0.14 0.18 0.14 0.43 0.49 0.50
90% Confidence interval
P
0.69–0.80 0.93–1.05 0.57–0.68 0.68–0.82 0.88–0.99 1.75–2.08 1.44–1.82 1.20–1.59
0.001 0.489 0.001 0.001 0.056 0.001 0.001 0.004
GMR, geometric mean ratio.
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Shah et al
FIGURE 5. Effects of concomitant administration of omeprazole (40 mg) on Cmax, AUC, Vd, and clearance of rosuvastatin in healthy volunteers (N 5 20).
elevation in the pH of the stomach.20 In the present study, the absorption half-life of the drug and bioavailability was not significantly changed. Therefore, this may also not be the pathway where bioavailability of the parent drug is not changed, whereas N-desmethyl metabolite was decreased by about 26%. Transporters-based clinically significant interactions have been reported between rosuva and other drugs that includes its interaction with gemfibrozil (OATP inhibitor),21 cyclosporine (OATP inhibitor), eltrombopag (OATP1B1 and BCRP inhibitor),22 lopinavir/ritonavir (BCRP and OATP inhibitor), and atazanavir/ritonavir (BCRP and OATP inhibitor).23 It is also possible that the omeprazole may inhibit the OATP transporters that in turn decrease the hepatic influx of the drug and may lead to reduced American Journal of Therapeutics (2015) 0(0)
metabolism of the drug. But in this case, the concentration of the parent drug will increase. However, the possibility of this phenomena is low because it should then increase the Cmax or AUC of the rosuva after concurrent administration with omeprazole, and in this case, no significant difference in these parameters were observed with simultaneous administration of rosuva and omeprazole. A relatively small increase has been observed in the ½AUCt0 and ½AUCN 0 values (4% and 2%, respectively) in our study after concomitant administration of rosuva with omeprazole; this may be due to a small decrease in the clearance that was also responsible for a slight increase (1%) in MRT value. A slight decrease in Cmax and increase in the AUC values have also been reported in DDI study of ketoconazole (CYP3A4 inhibitor) with rosuva.19 www.americantherapeutics.com
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Omeprazole-Rosuvastatin Interaction
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FIGURE 6. Effects of concomitant administration of omeprazole (40 mg) on Cmax, AUC, Vd, and clearance of NDMrosuva in healthy volunteers (N 5 20).
Omeprazole is substrate and inhibitor of P-gp.24 Although little, renal elimination of rosuva is governed by MDR-1, also called P-gp. Omeprazole may have inhibited rosuva’s elimination via renal route, leading to an increase in AUC (by 4%) and decrease in clearance (by 7%). The decrease in Vd can be attributed to changes in the protein binding because both rosuva and omeprazole are highly protein-bound drugs. Overall, the results from this study demonstrated the lack of PK-DDIs among rosuva and omeprazole in healthy volunteers. Any alterations in the PK parameters of rosuva after concomitant administration with omeprazole were of no clinical significance and are unlikely to increase its toxicity in usual therapeutic doses. Therefore, no adjustments in dosage regimens are warranted while coadministering omeprazole with rosuva. www.americantherapeutics.com
ACKNOWLEDGMENTS We are thankful to the University of Peshawar, Pakistan, and Strathclyde Institute of Pharmacy and Biomedical Sciences, Glasgow, United Kingdom, for providing the research facilities for analysis.
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10 3. Wierzbicki AS, Poston R, Ferro A. The lipid and non-lipid effects of statins. Pharmacol Ther. 2003;99: 95–112. 4. Davidson MH. Rosuvastatin: a highly efficacious statin for the treatment of dyslipidaemia. Expert Opin Investig Drugs. 2002;11:125–141. 5. McTaggart F, Jones P. Effects of statins on highdensity lipoproteins: a potential contribution to cardiovascular benefit. Cardiovasc Drugs Ther. 2008; 22:321–338. 6. Martin PD, Warwick MJ, Dane AL, et al. Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers. Clin Ther. 2003;25:2553–2563. 7. Martin PD, Warwick MJ, Dane AL, et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther. 2003;25:2822–2835. 8. Huang L, Wang Y, Grimm S. ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistance protein. Drug Metab Dispos. 2006;34:738–742. 9. Kitamura S, Maeda K, Wang Y, et al. Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008;36:2014–2023. 10. Cohen JP, Paquette C, Cairns CP. Switching prescription drugs to over the counter. BMJ. 2005;330:39–41. 11. Mears JM, Kaplan B. Proton pump inhibitors: new drugs and indications. Am Fam Physician. 1996;53:285. 12. Kennerley P, McColl KE. Proton pump inhibitors— differences emerge in hepatic metabolism. Dig Liver Dis. 2002;34:461–467. 13. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80:565–581. 14. Yang R, Schulman SG, Zavala PJ. Acid-base chemistry of omeprazole in aqueous solutions. Anal Chim Acta. 2003; 481:155–164.
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Effect of Omeprazole on the Pharmacokinetics of Rosuvastatin in Healthy Male Volunteers Yasar Shah, PhD,1* Zafar Iqbal, PhD,2 Lateef Ahmad, PhD,1 Fazli Khuda, MPhil,2 Abad Khan, PhD,1 Abbas Khan, PhD,1 Muhammad Imran Khan, PhD,2 and Ismail, PharmD2
The current study aimed at the evaluation of, in vivo, the effect of omeprazole on the pharmacokinetics of rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Omeprazole is an acid suppressant and CYP2C9, CYP3A4, and CYP2C19 substrate and inhibitor, as well as inhibitor of transporters (like P-gp). This was a randomized, open-label, 2-period, crossover study. Healthy male volunteers (N 5 20), divided into 2 groups, were given single oral doses of rosuvastatin 40 mg either alone (treatment period I) or concomitantly with omeprazole 40-mg capsule (treatment period II). Plasma concentrations of rosuvastatin (rosuva) and its metabolite N-desmethyl rosuvastatin (NDM-rosuva) were quantified by a validated liquid chromatography– tandem mass spectrometry method developed in our laboratory. An insignificant decrease (P . 0.05) has been observed in the values of maximum plasma concentrations, clearance, and half-life of rosuva, whereas an insignificant increase (P . 0.05) has been observed in the area under the plasma concentration–time curves from zero time to the last measurable concentration½AUCt0 , that extrapolated to infinity ½AUCN 0 , and mean residence time values after concomitant administration with omeprazole. Although omeprazole concomitant administration altered the pharmacokinetics of NDM-rosuva metabolite significantly, rosuva’s very little metabolism (10%) suggests that these changes are of no clinical significance. Concomitant administration of omeprazole with rosuva did not alter the pharmacokinetics of rosuva in healthy volunteers. These data are consistent with other reported studies, indicating that rosuva is not a good candidate for metabolism-based drug–drug interactions. Therefore, rosuva can be administered safely along with omeprazole. Keywords: rosuvastatin, pharmacokinetics, omeprazole, drug–drug interaction
INTRODUCTION Rosuvastatin (rosuva) (Figure 1) is a highly effective statin drug that strongly inhibits the 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase involved in cholesterol biosynthesis in vivo and is
1
Department of Pharmacy, University of Swabi, Swabi, Pakistan; and 2Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. The authors have no conflicts of interest to declare. *Address for correspondence: Assistant Professor, Department of Pharmacy, University of Swabi, Swabi, KPK-Pakistan. E-mail: [email protected]
used to treat hypercholesterolemia and other lipid disorders. Rosuva exerts its effects by causing reduction in the low-density lipoprotein C, total cholesterol, and triglycerides levels and elevation in the high-density lipoprotein C level.1–5 Rosuva gets its absorption from the acidic environment of the stomach and has an estimated absolute oral bioavailability of approximately 20% and absorption of 50%. It is a highly plasma protein–bound drug (88%).6 Metabolism is the minor route accounting for its elimination. Only 10% of the parent drug undergoes metabolism forming an active metabolite, that is, N-desmethyl rosuvastatin (NDM-rosuva) (Figure 1) and an inactive metabolite, that is, rosuvastatin-5Slactone (Figure 1). CYP2C9 isozyme is primarily
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Shah et al
2
FIGURE 1. Rosuva metabolism (structures of parent drug and metabolites).
involved, although CYP3A4 and CYP2C19 have little contribution in metabolism.7 About 90% of the administered dose is usually recovered in the feces unchanged.7 Rosuva absorption, hepatic uptake, and biliary and renal excretion are governed by several transporters, and recent researches have shown that transporters play a vital role in the pharmacokinetic drug–drug interaction (PK-DDI) between 2 drugs. Breast cancer resistance protein (BCRP) is an efflux transporter involved in its intestinal transport,8 whereas organic anion-transporting polypeptides (ie, OATP1B1, OATP1B3, and OATP2B1) and sodium taurocholate cotransporting polypeptide (NTCP) are involved in its hepatic uptake.8,9 Transporters involved in its biliary excretion are multidrug resistance protein 1 (MDR1), multidrug resistance associated protein 2 (MRP2), BCRP, and bile salt exporter protein,8,9 whereas renal excretion occurs through MDR1 (or P-gp).9 Omeprazole, being a prototype of proton pump inhibitors, is prescribed mostly for gastrointestinal tract disturbances, including hyperacidity and gastroesophageal reflux disease.10,11 It is basic in nature, and metabolism occurs primarily through CYP2C19 and American Journal of Therapeutics (2015) 0(0)
CYP3A4.12 It is also a strong inhibitor of these enzymes and also a substrate of drug transporters, like BCRP. CYP3A4 inhibitors also have potential of inhibiting transporters like OATP.13 Rosuva is acidic in nature with a pKa value of 4.46, and omeprazole is basic with pKa values of 7.1 and 14.7,14 and little metabolism of rosuva by the same group of enzymes, that is, CYP2C19 and CYP3A4, that are also responsible for omeprazole metabolism may account for a possible PK-DDI between them. The possibility of transporters-based interaction cannot be ruled out as well. Therefore, potential drug interaction between omeprazole and rosuva is possible and that needs to be evaluated. So far, no PK-DDI between rosuva and omeprazole in humans has been reported. The aim of the current study was to evaluate the effect of concomitant administration of omeprazole on rosuva pharmacokinetics in healthy volunteers.
SUBJECTS AND METHODS Trial population The PK-DDI between rosuva and omeprazole was assessed in normal healthy male volunteers (N 5 20). www.americantherapeutics.com
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Omeprazole-Rosuvastatin Interaction
Their mean 6 SD of age, weight, and height were 26.05 6 2.52 years (range, 22–31 years), 64.0 6 2.47 kg (range, 60–68 kg), and 65.95 6 1.79 inches (range, 63–69 inches), respectively. The local Ethical Committee of Department of Pharmacy, University of Peshawar approved the protocol before initiation. This study was conducted in accordance with the “ethical principles of the Helsinki Declaration for medical research involving human subjects” and “Good Clinical Practice Guidelines.” Being an open-label study, all the factors from dosing till sampling procedures were explained to the volunteers after which they signed a written consent. Inclusion and exclusion criteria A strict inclusion and exclusion criteria was adopted for the eligibility of volunteers in this study. The healthy status of the participants was confirmed by conducting a detailed physical examination and obtaining complete medical history. Thorough clinical examination process including different important biochemical tests like low-density lipoprotein, highdensity lipoprotein, and triglyceride profiles and electrocardiography was performed for all the participants. Other clinical tests included liver function tests, renal function tests, blood pressure, and blood glucose level. The results of all these examinations and tests were in normal ranges, indicating their good health. Subjects having any disease like coronary heart disease, chronic renal disease, diabetes mellitus, hepatic impairment, or any other systemic pathology were excluded from this study. Subjects who were obese and smokers were also excluded because these factors also contribute to the imbalance in the lipid profile. Subjects using any type of medicines and those on special diets were also excluded. Any volunteers expressing hypersensitivity to any of the drug in this particular study were also excluded. Study design It was designed as a single-dose, randomized, 2-sequence, 2-treatment period, and crossover study with 2-week washout time in between. Rosuva either alone (40 mg) or in combination with omeprazole (rosuva 40 mg + omeprazole 40 mg) was administered to the eligible volunteers (divided in 2 groups) according to the design as presented in Table 1. The details of drug products administered to the volunteers in their specified doses and dosage forms are provided in Table 2. Drug administration Volunteers were randomly distributed in 2 groups: group I and group II. The volunteers were kept abstain www.americantherapeutics.com
3 Table 1. Study design for PK-DDI study of rosuva and omeprazole in healthy human volunteers. Treatment sequences Sequence 1
2-Week washout period Sequence 2
Group I (n 5 10)
Group II (n 5 10)
Rosuvastatin alone Rosuvastatin + omeprazole (oral tablet, dose: (rosuva oral 40 mg) tablets, dose: 40 mg and omeprazole oral capsules, dose: 40 mg)
Rosuvastatin + omeprazole (rosuva oral tablets, dose: 40 mg and omeprazole oral capsules, dose: 40 mg)
Rosuvastatin alone (oral tablet, dose: 40 mg)
from not taking any medication and were advised to fast overnight to follow the standard protocol. Rosuva and omeprazole were administered to the volunteers according to the sequences described in the Table 1. In the first sequence, group I received rosuva (2 3 20 mg tabs), whereas group II received omeprazole (2 3 20 mg capsules) along with rosuva (2 3 20 mg tabs). In the second sequence, after allocating a 1-week washout period, group I received omeprazole (2 3 20 mg capsules) along with rosuva (2 3 20 mg tabs), whereas group II received rosuva (2 3 20 mg tabs) only. To maintain uniformity and standard protocol, these mentioned drugs were administered with 1 glass full of water (250 mL). The participants were not allowed to have juices or drinks other than water during the study period, and only breakfast and lunch were served 2.0 and 6.0 hours after drug administration, respectively. Blood sampling and collection of plasma Blood samples (approximately 5 mL) for the assay of rosuva and NDM-rosuva were collected in heparinized tubes just before the first intake of rosuva (either alone or in combination with omeprazole) and at intervals of 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12, and 24 hours post dose. Plasma was separated and collected by centrifugation of the noncoagulated blood samples and then stored at 280°C until analysis. While handling and performing other experimental procedures, protection from heat and excessive light was ensured. American Journal of Therapeutics (2015) 0(0)
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Shah et al
4 Table 2. Drug products utilized in PK-DDI study of rosuva and omeprazole. Product (Trade name)
Manufacturer
Batch number
Date of manufacture
Expiry date
Aurora (rosuvastatin; 20 mg/tablet) Omega (omeprazole; 20 mg/capsule)
Ferozsons Labs Pvt, Ltd, Nowshera, Pakistan Ferozsons Labs Pvt, Ltd, Nowshera, Pakistan
9E 135
March, 2013
March, 2015
9E 179
March, 2013
March, 2016
Samples analysis for determination of rosuva and NDM-rosuva Plasma samples were analyzed for rosuva and NDMrosuva by a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) developed in our laboratory. The plasma samples collected and stored at 280°C were thawed at room temperature at the time of analysis, and drugs were extracted with a simple 1-step liquid–liquid extraction procedure using acetonitrile. The lower limit of detection and lower limit of quantification for rosuva were 0.1 and 0.2 ng/mL, whereas for NDM-rosuva, these were 0.03 and 0.1 ng/mL, respectively. The analytes were efficiently separated on HiChrom C18 (150 3 3.0 mm, 3 mm; Reading, United Kingdom) column using 0.1% formic acid in acetonitrile and 0.1% formic acid in water (70:30 vol/vol) as a mobile phase and pumped at a flow rate of 300 mL/min. A high-resolution Thermo Electron Corporation LTQ-Orbitrap mass spectrometer (San Jose, CA) was used, operated in positive ion mode with the m/z ranges set for rosuva, NDM-rosuva, and atorvastatin (internal standard) as 482.1750–482.1780, 468.1590–468.1610, and 559.2595– 559.2625 (amu), respectively. The capillary temperature was 275°C, whereas the source and capillary voltages were 4.5 kV and 35 V, respectively. The auxiliary and sheath gases were 15 and 50 (arbitrary units), respectively, and the column oven temperature and sample injection volume were 25°C and 10 mL, respectively. Correlation coefficients for both rosuva and NDM-rosuva were 0.999. The average %recoveries were above 96.0% and 98.0% for rosuva and NDM-rosuva, respectively, whereas % relative standard deviation values for both analytes were less than 1%, indicating accuracy of the method. Pharmacokinetic evaluation The pharmacokinetic parameters were calculated by a noncompartmental pharmacokinetic approach using PK Solutions (version 2.0.2; Summit Research Services, Ashland, OH). The maximum plasma concentrations (Cmax) and time to reach Cmax (Tmax) were observed directly from the plasma concentration versus time profiles and measured data of rosuva and American Journal of Therapeutics (2015) 0(0)
NDM-rosuva. Linear trapezoidal rule was utilized for the calculation of area under the plasma concentration–time curves from zero time to the last measurable concentration ½AUCt0 , whereas extrapolated to infinity ½AUCN 0 was calculated using the equation: t ½AUCN 5 ðAUC 0 þ Ct Þ=ke, where Ct is the last quan0 tifiable concentration of the drug in plasma. The elimination half-life (t1/2) was then calculated as 0.693/ke. ke is the elimination rate constant determined as the slope of the terminal portion of elimination phase of plasma concentration–time curve using linear least square regression. Statistical data interpretation The pharmacokinetic data of rosuva and its metabolite NDM-rosuva obtained from this study were analyzed statistically by the SPSS software (version 16.0; SPSS, Inc, Chicago, IL). The PK parameters were expressed as mean 6 SD. Geometric mean ratios for the treatment (rosuva plus omeprazole/rosuva alone) were calculated, and 95% confidence intervals of the mean were determined. A paired t test was performed for the comparison of PK parameters between rosuva plus omeprazole and rosuva alone treatments. P , 0.05 value was considered statistically significant.
RESULTS The plasma concentrations of rosuva and NDMrosuva were determined in healthy volunteers treated either with rosuva 40-mg oral tablet alone or in combination with omeprazole 40-mg oral capsule using the developed and validated LC-MS/MS method. A typical LC-MS/MS chromatogram of real plasma sample showing peaks and ion spectras of rosuva, NDM-rosuva, and internal standard (atorvastatin) is presented in Figure 2. The plasma concentrations of rosuva and NDM-rosuva were plotted against time on both linear (normal) and semilog graph papers (presented in Figures 3, 4). A PKspecific software, that is, PK-Summit software (version 2.0.2; PK Solutions) and Microsoft Excel were used for the determination and evaluation of PK www.americantherapeutics.com
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Omeprazole-Rosuvastatin Interaction
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FIGURE 2. Representative LC-MS/MS chromatogram of a human plasma sample treated with 40 mg of rosuvastatin showing peaks and ion spectras of rosuva, NDM-rosuva, and atorvastatin (internal standard).
parameters of rosuva and NDM-rosuva. The determined PK parameters are summarized and presented in Tables 3 and 4. PK parameters of rosuvastatin After coadministration with omeprazole 40-mg capsule, an insignificant decrease (P . 0.05) in the Cmax value of rosuva was observed as compared with rosuva administration alone. The value of tmax remained the same in both the treatments, whereas the values of ½AUC24 0 (in mean 6 SD), ½AUCN (in mean 6 SD), and mean resi0 dence time (MRT) (in mean 6 SD) of rosuva increased insignificantly (P . 0.05). The volume of distribution of rosuva decreased significantly (P , 0.05), whereas clearance and t1/2-b value decreased insignificantly (P . 0.05) in volunteers treated with omeprazole along with rosuva compared with rosuva administration alone. Results are graphically presented in Figure 5. www.americantherapeutics.com
PK parameters of NDM-rosuva Peak plasma concentrations (Cmax), ½AUC24 0 , and N ½AUC0 of NDM-rosuva decreased significantly (P , 0.05), whereas Vd, clearance, and elimination half-life values increased significantly (P , 0.05) after concomitant administration of omeprazole as compared with rosuva administration alone. A slight insignificant decrease (P . 0.05) was observed in the tmax and MRT values of NDM-rosuva after concomitant administration of omeprazole with rosuva in comparison to its administration alone. The results are graphically presented in Figure 6.
DISCUSSION Extensive work has been carried out by researchers for assessing the potential of DDI between rosuva and other drugs. The impact of other drugs over the American Journal of Therapeutics (2015) 0(0)
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FIGURE 3. Plasma concentration versus time plot of rosuvastatin in healthy human volunteers (N 5 20) after administration of rosuvastatin alone (40 mg) and in combination with omeprazole (40 mg). (A) Linear graph. (B) Semilog graph.
pharmacokinetics of rosuva is well studied, taking into consideration the metabolism (although rosuva undergoes little metabolism via CYP2C9, CYP2C19, and CYP3A4) and mainly transporters. Omeprazole is primarily metabolized by CYP2C19, CYP3A4, and CYP2C9. It is also a strong inhibitor of these enzymes.15 Furthermore, omeprazole is an acid
suppressive agent and also is a basic drug in nature, whereas the metabolism of rosuva (although little) is catalyzed by CYP2C9, CYP2C19, and CYP3A4. Rosuva is acidic in nature having pKa of 4.46. These common metabolizing enzymes provided the basis for conducting and evaluating the PK-DDI studies of rosuva and omeprazole.
FIGURE 4. Plasma concentration versus time plot of NDM-rosuva in healthy human volunteers (N 5 20) after administration of rosuvastatin alone (40 mg) and in combination with omeprazole (40 mg). (A) Linear graph. (B) Semilog graph. American Journal of Therapeutics (2015) 0(0)
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Omeprazole-Rosuvastatin Interaction
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Table 3. Pharmacokinetic parameters of rosuvastatin after concomitant administration with omeprazole (40 mg) and after administration of rosuvastatin alone (40 mg).
PK parameters of rosuva Cmax (ng/mL) Tmax (h) ½AUCt0 (ng$h/mL) ½AUCN 0 (ng$h/mL) MRT (h) Vd (mL/kg) CL (mL$h21/kg) E half-life (h)
Rosuva administration alone (mean 6 SD) 28.62 3.05 202.86 209.25 5.76 20,036.54 3269.05 4.06
6 6 6 6 6 6 6 6
5.31 0.22 25.99 28.02 0.60 5570.01 741.38 0.42
Rosuva + omeprazole administration (mean 6 SD) 28.05 3.05 210.38 212.86 5.82 16,563.34 3052.75 3.81
6 6 6 6 6 6 6 6
5.00 0.22 27.50 27.57 0.30 3916.52 655.96 0.44
GMR (mean 6 SD)
90% Confidence interval
P
6 6 6 6 6 6 6 6
0.96–1.01 0.97–1.04 1.01–1.07 1.00–1.04 0.97–1.07 0.80–0.90 0.90–0.98 0.92–0.96
0.728 1.0 0.380 0.683 0.647 0.025 0.335 0.081
0.98 1.00 1.04 1.02 1.01 0.84 0.94 0.94
0.06 0.10 0.08 0.04 0.12 0.14 0.10 0.04
GMR, geometric mean ratio.
A slight but insignificant decrease in the Cmax value (2%) of rosuva was observed after concomitant administration of omeprazole 40-mg capsule with rosuva 40-mg tablet, which is practically considered to be of no clinical significance. But the Cmax value of NDM-rosuva (metabolite) decreased significantly (26%), reflecting that rosuva metabolism decreased when rosuva was administered along with omeprazole. The reason for this may be the inhibition of enzymes responsible for rosuva metabolism, that is, CYP2C19 and CYP3A4 by omeprazole, due to the fact that omeprazole is the substrate and inhibitor of these enzymes. However, as rosuva undergoes a very little total metabolism (;10%), therefore, inhibition of rosuva metabolism by concomitant administration of omeprazole is of less clinical significance. Clinically insignificant DDIs have been reported so far between rosuva and other drugs underlying the
mechanism of enzyme induction or inhibition, indicating a little potential of rosuva for metabolismbased PK-DDIs.16,17 Fluconazole (CYP2C9 and CYP219 inhibitor), erythromycin (CYP3A4 inhibitor), itraconazole (CYP3A4 inhibitor), rifampicin, and ketoconazole (CYP2C9 inducers) did not alter the PK of rosuva significantly.18,19 The slight decrease in the Cmax of rosuva may be due to the fact that omeprazole is an acid suppressant and rosuva being an acidic drug having better absorption in acidic media, concomitant administration of omeprazole along with rosuva may decrease its absorption by elevating the gastric pH and increasing the ionization of rosuva. A DDI study reported a decrease in the absorption and bioavailability of rosuva after concomitant administration of antacid preparation (aluminium hydroxide and magnesium hydroxide) and that may be due to the
Table 4. Pharmacokinetic parameters of NDM-rosuva after concomitant administration with omeprazole (40 mg) and after administration of rosuvastatin alone (40 mg).
PK parameters of NDM-rosuva
Rosuva administration alone (mean 6 SD)
Cmax (ng/mL) Tmax (h) ½AUCt0 (ng$h/mL) ½AUCN 0 (ng$h/mL) MRT (h) Vd (mL/kg) CL (mL$h21/kg) E half-life (h)
1.73 3.9 5.38 7.02 4.27 202,818.33 105,181.75 1.50
6 6 6 6 6 6 6 6
0.40 0.31 1.21 1.74 0.52 42,745.02 24,496.29 0.29
Rosuva + omeprazole GMR administration (mean 6 SD) (mean 6 SD) 2.34 4.0 8.69 9.41 4.65 106,399.22 65,279.10 1.18
6 6 6 6 6 6 6 6
0.37 0.56 0.86 0.87 0.35 22,512.92 15,427.29 0.39
0.73 0.98 0.61 0.73 0.93 1.86 1.56 1.33
6 6 6 6 6 6 6 6
0.15 0.16 0.14 0.18 0.14 0.43 0.49 0.50
90% Confidence interval
P
0.69–0.80 0.93–1.05 0.57–0.68 0.68–0.82 0.88–0.99 1.75–2.08 1.44–1.82 1.20–1.59
0.001 0.489 0.001 0.001 0.056 0.001 0.001 0.004
GMR, geometric mean ratio.
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Shah et al
FIGURE 5. Effects of concomitant administration of omeprazole (40 mg) on Cmax, AUC, Vd, and clearance of rosuvastatin in healthy volunteers (N 5 20).
elevation in the pH of the stomach.20 In the present study, the absorption half-life of the drug and bioavailability was not significantly changed. Therefore, this may also not be the pathway where bioavailability of the parent drug is not changed, whereas N-desmethyl metabolite was decreased by about 26%. Transporters-based clinically significant interactions have been reported between rosuva and other drugs that includes its interaction with gemfibrozil (OATP inhibitor),21 cyclosporine (OATP inhibitor), eltrombopag (OATP1B1 and BCRP inhibitor),22 lopinavir/ritonavir (BCRP and OATP inhibitor), and atazanavir/ritonavir (BCRP and OATP inhibitor).23 It is also possible that the omeprazole may inhibit the OATP transporters that in turn decrease the hepatic influx of the drug and may lead to reduced American Journal of Therapeutics (2015) 0(0)
metabolism of the drug. But in this case, the concentration of the parent drug will increase. However, the possibility of this phenomena is low because it should then increase the Cmax or AUC of the rosuva after concurrent administration with omeprazole, and in this case, no significant difference in these parameters were observed with simultaneous administration of rosuva and omeprazole. A relatively small increase has been observed in the ½AUCt0 and ½AUCN 0 values (4% and 2%, respectively) in our study after concomitant administration of rosuva with omeprazole; this may be due to a small decrease in the clearance that was also responsible for a slight increase (1%) in MRT value. A slight decrease in Cmax and increase in the AUC values have also been reported in DDI study of ketoconazole (CYP3A4 inhibitor) with rosuva.19 www.americantherapeutics.com
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Omeprazole-Rosuvastatin Interaction
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FIGURE 6. Effects of concomitant administration of omeprazole (40 mg) on Cmax, AUC, Vd, and clearance of NDMrosuva in healthy volunteers (N 5 20).
Omeprazole is substrate and inhibitor of P-gp.24 Although little, renal elimination of rosuva is governed by MDR-1, also called P-gp. Omeprazole may have inhibited rosuva’s elimination via renal route, leading to an increase in AUC (by 4%) and decrease in clearance (by 7%). The decrease in Vd can be attributed to changes in the protein binding because both rosuva and omeprazole are highly protein-bound drugs. Overall, the results from this study demonstrated the lack of PK-DDIs among rosuva and omeprazole in healthy volunteers. Any alterations in the PK parameters of rosuva after concomitant administration with omeprazole were of no clinical significance and are unlikely to increase its toxicity in usual therapeutic doses. Therefore, no adjustments in dosage regimens are warranted while coadministering omeprazole with rosuva. www.americantherapeutics.com
ACKNOWLEDGMENTS We are thankful to the University of Peshawar, Pakistan, and Strathclyde Institute of Pharmacy and Biomedical Sciences, Glasgow, United Kingdom, for providing the research facilities for analysis.
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