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A Retrospective, Open-Label Analysis of the Population Pharmacokinetics of a Single 10-mg Dose of Loratadine in Healthy White Jordanian Male Volunteers
Isam I. Salem, PhD1; Naji M. Najib, PhD1; and Nasir M. Idkaidek, PhD2
Pharmaceutical Research Center, Amman, Jordan; and 2College of Pharmacy, University of Petra, Amman, Jordan
Background: Loratadine is a long-acting tricyclic antihistamine with selective peripheral histamine H1-receptor antagonist activity. Loratadine 10-mg tablets have been reported to be rapidly absorbed after once-daily administration for 10 days in healthy adult subjects, with a Tmax of 1.3 hours for loratadine and 2.5 hours for its major active metabolite, descarboethoxyloratadine. The t1/2 in normal adult subjects has been reported to be 8.4 hours (range, 3–20 hours) for loratadine and 28 hours for its metabolite. Objective: The aim of this study was to determine the population pharmacokinetics of loratadine after oral administration. Methods: A retrospective analysis was conducted of prior noncompartmental analysis results from healthy white Jordanian male subjects who participated in 2 pharmacokinetic studies. After a 10-hour overnight fast, a single 10-mg loratadine tablet was administered orally followed by 240 mL of water. Blood samples were collected before dosing and at 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours after dosing. Mean and population plasma level profiles were examined. The calculated primary and secondary pharmacokinetic parameters were Vd/F, ke, absorption rate constant, lag time, distribution rate constant, redistribution rate constant, Tmax, and Cmax. Results: A total of 72 healthy male subjects with a mean (SD) age of 23 (3.57) years participated in the 2 studies. The analytical method was linear over the concentration range from 0.10 to 20.00 ng/mL (r > 0.999). The lower limit of quantitation was 0.1 ng/mL with 95% accuracy. Precision, expressed as %CV, was 7.44%. Intraday accuracy ranged from 91.9% to 97.2% at high and low quality control levels, respectively. Interday accuracy ranged from 93.57% (%CV, 4.35%) to 98.78% (%CV, 5.78%), respectively. Population ke, t1/2, absorption rate constant, and absorption t1/2 were February 2010 0.19 hour–1, 3.65 hours, 1.31 hours–1, and 0.53 hour, respectively. Distribution rate constant, redistribution rate constant, and lag time were 0.31 hour–1, 0.02 hour–1, and 0.32 hour, respectively. The noncompartmental estimate for Cmax was 3.02 ng/mL, which occurred at 1.30 hours, with a t1/2 of 5 hours and a ke of 0.14 hour–1. No adverse events were recorded during the study. Conclusion: The population t1/2 for loratadine was 3.65 hours in this group of healthy white Jordanian male volunteers, shorter than that observed in previous research. (Clin Ther. 2010;32:391–395) © 2010 Excerpta Medica Inc. Key words: population, pharmacokinetics, loratadine, half-life, HPLC-MS/MS.
Loratadine is a long-acting tricyclic antihistamine with selective peripheral histamine H1-receptor antagonist activity. Loratadine 10-mg tablets have been reported to be rapidly absorbed after once-daily administration for 10 days in healthy adult subjects, with a Tmax of 1.3 hours for loratadine and 2.5 hours for its major active metabolite, descarboethoxyloratadine. The pharmacokinetics of loratadine and its metabolite are dose independent over the dose range from 10 to 40 mg.1–3 It has been reported that ~80% of the total loratadine dose is equally distributed between urine and feces in the form of metabolic products within 10 days.1–4 Exposure to the metabolite is greater than exposure to the parent compound. The t1/2 in normal adult subjects has been reported to be 8.4 hours (range, 3–20 hours) for loratadine and 28 hours for its
Accepted for publication October 22, 2009. doi:10.1016/j.clinthera.2010.02.001 0149-2918/$ - see front matter © 2010 Excerpta Medica Inc. All rights reserved.
or require hospitalization within 3 months before initiation of both studies. and the presence of illegal drugs.11 > *Trademark: Claritin® (Schering-Plough Healthcare Products Inc. Blood samples were centrifuged for 5 minutes at 1789g and stored at –20°C until analysis. hepatitis B and C viruses. New Jersey. methanol. In both studies. expiration date. Electrospray ionization in the positive mode was used to ionize the analytes. including over-the-counter drugs. Drugs and Reagents Loratadine 10-mg tablets (batch #00A1101. The parameters ke.. and the subjects were questioned about adverse events by the investigators. 4. and 96 hours after dosing. ECG. 8. 12.5.3 hours. 6.1–4 The authors of the present study have conducted unpublished pharmacokinetic research in humans after oral dosing of loratadine at the International Pharmaceutical Research Center (IPRC) in Amman. no detailed data analysis of loratadine on population pharmacokinetics has been published. Belgium. 1. 24. France). for 7 days before the study. 1. Through 2009. The search covered up to 2009. 16. The subjects were under continuous medical observation by the investigators and attending physicians during both studies. The population pharmacokinetic approach is used to obtain integrated information on pharmacokinetics. batch #32007.A. Jordan. This was confirmed by a search of MEDLINE using several combinations of the terms loratadine. the objective of the present study was to determine the population pharmacokinetics of loratadine by simultaneous data-fitting of prior noncompartmental analysis results from 72 subjects who participated in 2 pharmacokinetic studies. such as concentration data obtained from pediatric and elderly patients. 3.Clinical Therapeutics metabolite. renal. SUBJECTS AND METHODS Healthy white Jordanian male subjects gave written informed consent to participate in the 2 studies before screening. The studies were approved by the Institutional Review Board at IPRC and were performed in accordance with the Good Clinical Practice guideline and the Declaration of Helsinki. Subjects Male volunteers included in the 2 pharmacokinetic studies were within 15% of their ideal body weight and were judged to be healthy based on medical history. serum chemistry. 2. acetonitrile. Molshiem. 392 Volume 32 Number 2 . Variability in loratadine pharmacokinetic data has been observed in published studies of loratadine tablets and syrup. and consisted of liquid–liquid extraction and separation on a reverse-phase C18 analytical column. Six batches of lithium heparin plasma were obtained from healthy blood donors who were HIV and hepatitis B and C negative. Subjects were negative for HIV.5 It also allows the analysis of data from a variety of unbalanced designs. Therefore. physical examination. possibly because of the drug’s extensive first-pass metabolism. Plasma samples were analyzed at IPRC using a validated HPLC-MS/MS method. Blood samples (7 mL) were collected in heparinized tubes from an indwelling catheter in the antecubital vein of the forearm before dosing and at 0. a single 10-mg loratadine tablet was administered orally followed by 240 mL of water. Water was purified using a Milli-Q integral water purification system (Millipore S. These authors used a radioimmunoassay with a lower limit of quantitation (LLOQ) of 0. biochemistry. physical examination. and Cmax were compared with the population analysis. donate blood. Experimental and Assay Procedures In both studies. no subjects took any medication. 36. or gastrointestinal conditions. and population. 72. hematology.33. respiratory. Chromatograms were extracted at 383. respectively). Heist-op-den-Berg. after a 10-hour overnight fast. Tmax. January 2003.S.2 to 36. cardiac. complete blood count. 48. the calculated t1/2 was observed to be shorter than that previously reported for this drug. Follow-up medical testing (vital signs.66. as well as data from studies that may otherwise be excluded because they do not lend themselves to the usual forms of pharmacokinetic analysis. April 2003*) were purchased from local suppliers. expiration date. and urinalysis) was conducted on all volunteers at discharge from both studies.3 ng/mL. The subjects did not participate in any other clinical study. formic acid) were all analytical grade for HPLC use.. and lack of hepatic. pharmacokinetics. or data obtained from evaluation of the relationships between dose and concentration or efficacy and tolerability. Chemicals and reagents (eg.6 The method was modified by readjusting the mobile phase composition. and Kenilworth. In these studies. 0. 10.1–3 Hilbert et al4 conducted a 3-way crossover study of loratadine in healthy volunteers and reported that the loratadine t1/2 ranged from 4.
65 k12. The LLOQ was 0. In addition. was 7.02 (96) 1. expressed as %CV. A modified Gauss-Marquardt algorithm was used under uniform weighting and the Marquardt algorithm converged after 12 iterations. †C max and Tmax values were determined directly from each subject profile. improvement in residual plots. h–1 0.03) k 01. Precision. Tmax. *t1/2 values were calculated using the formula: 0. h* 0. RESULTS Seventy-two healthy male subjects (36 in each of the 2 studies) with a mean (SD) age of 23 (3. and the parameters ke. distribution rate constant (k12).1 ng/mL with 95% accuracy. posterior population mean and variance were computed. ng/mL† – Tmax. simultaneous data-fitting was conducted using Kinetica version 4.2% at high and low quality control levels. Further applications of this algorithm are possible in linear mixed-effect models with fewer assumptions in the variance models and either maximum likelihood or restricted maximum likelihood estimation.78% (%CV. respectively. Population and Noncompartmental Analysis In this retrospective analysis of prior noncompartmental analysis results. a noncompartmental analysis was performed for each subject. and prediction of the individual and population profiles. The analytical method was linear over the concentration range from 0. h† – Vd/F. weighting schemes. h–1 0.8–10 No further assumptions were used.19 (72) t1/2. No adverse events were recorded during the studies. The HPLC-MS/MS method was validated according to the US Food and Drug Administration’s bioanalytic method validation guidance.7 software enabled evaluation of the distribution of computed parameters and the residual error.78%). Then.32 (19) k12 = distribution rate constant. k 21 = redistribution rate constant. Salem et al.I. h–1 0.31 (116) Absorption t1/2. Intraday accuracy ranged from 91.57) years were included in this analysis.20 m/z. ke.I. lag time. 5. improvement in objective function. The individual parameters in the model were estimated assuming that they had known prior and residual error distributions. h* 3. and the log-likelihood test. Data Analysis A 2-compartment model was employed for population data-fitting using 6 parameters: Vd/F. Kinetica is a software package for population pharmacokinetic analysis that uses an expectation-maximization (EM) algorithm to conduct nonlinear mixed-effect model analysis. None of the subjects had clinically relevant changes in vital signs after administration of the study drug.44%. L 2147 (0. This is a 2-step algorithm comprised of an E-step (expectation) and an M-step (maximization). k 01 = absorption rate constant.14 (44) 5.10 to 20. the Schwarz criterion. Waltham. and Cmax were reported for comparisons. and then computed the appropriate statistical tests to evaluate the distribution properties of the differences between the expected and observed data.31 (241) k 21. 337.00 ng/mL (r > 0. h 0.57% (%CV. given the individual parameter values. Massachusetts).53 Lag time.693/k. The M-step obtains the maximum likelihood posterior population mean and variance together with the residual error variance. with the option to display the CI. We estimated the expected individual parameters given the population’s estimated values. Interday accuracy ranged from 93. absorption rate constant (k01).1 (Thermo Electron Corporation. The EM algorithm is an iterative procedure developed for finding maximum likelihood estimates for incomplete data. The evaluation graphs in the February 2010 Table. and statistical tests including the Akaike criterion. The E-step uses current values for parameter estimates to obtain the expectation of individual parameters conditioned by the observed data vector.02 (81) Cmax. Mean (%CV) loratadine pharmacokinetic parameters after a 10-mg oral dose in healthy white Jordanian male volunteers (N = 72). and redistribution rate constant (k21). 393 . Mean and popula- Model Building The criteria used for model building included examination of the fitted curves. 4.0 – – 3.30 (55) – – – – ke. Population and noncompartmental parameter estimates are summarized in the table. h–1 1. Parameter Population Value Noncompartmental Value 0.999).9% to 97.35%) to 98.
0 1. Population ke. and 0. and lag time were 0.30 hours.65 hours.31 hour–1. respectively.1. 0.0 2. A Plasma Concentration (ng/mL) DISCUSSION The population pharmacokinetics of loratadine were evaluated by simultaneous fitting of data from 72 healthy white Jordanian men who participated in 2 pharmacokinetic studies.02 hour–1. The Cmax was 3.19 hour–1.Clinical Therapeutics tion plasma level profiles with 95% CI are shown in the figure. Thermo Electron Corporation. 3. Massachusetts) after 10-mg oral dose in healthy white Jordanian male volunteers (N = 72).02 ng/mL and the Tmax was 1.31 hours–1. and 1. Waltham. 394 Volume 32 Number 2 .5 1.5 2. The goodness-of-fit figures suggest that residuals were of random and homogeneous dis- 3. and k01 values were 0.32 hour.0 0. The k12. t1/2. k21. respectively.5 3. (A) Mean plasma concentration–time curve and (B) output curve of all individual data for plasma concentrations (Kinetica version 4.5 0 0 20 40 60 80 100 Undetectable Outlier Time (h) B 6 4 Plasma Concentration (ng/mL) 2 0 –2 0 20 40 60 80 100 Time (h) Figure. and Vd/F was 2147 L.
et al. Al Tamimi JI. 6.5 hours. Center for Biologics Evaluation and Research. 15th ed.27:694–698.34:141–151. February 1999. May 2001. Louis. 3.jo February 2010 395 . Food and Drug Administration. tribution up to the Cmax of 3. Martindale: The Complete Drug Reference. shorter than the 7. 1987. http://www. the estimates of all parameters were in agreement with the noncompartmental analysis results presented. Center for Drug Evaluation and Research. US Dept of Health and Human Services.1–4 A limitation of this study is that population parameter estimates were limited to white Jordanian male volunteers. Zhang YF.1–4 However. Salem II. Salem et al.02 ng/mL. J Clin Pharmacol. J Pharm Biomed Anal. 2010. 9.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM070107. Pharmacokinetics of loratadine and its active metabolite descarboethoxyloratadine in healthy Chinese subjects. Hilbert J. Food and Drug Administration.pdf. 2001. More volunteers from different national groups should be included to account for possible ethnic differences in future studies. PO Box 963166. Sports City Circle. Amman 11196. Guidance for Industry. NJ: Medical Economics Co. Calculated and observed points were well correlated with each other up to the Cmax. as indicated by population %CV. 4. 5. The large Vd/F indicates wide tissue distribution. 2010. Biopharm Drug Dispos. St. Determination of population pharmacokinetic parameters of sustainedrelease and enteric-coated oral formulations. Montvale. Idrees J. nurses. E-mail: dr. Idkaidek NM. Pharmacokinetics and dose proportionality of loratadine. PhD. CONCLUSION In the present study conducted in healthy white Jordanian male volunteers. Physicians’ Desk Reference. ed. International Pharmaceutical Research Center.19:169–174.65 to 5 hours. chemists. 8. was generally >30%. Sweetman SC. the large k01 and small lag-time estimates were in agreement with the small Tmax value. Radwanski E. Accessed January 25. 34th ed. Mo: Mosby. Salem. Ill: Pharmaceutical Press. Zhong DF. UK. and Chicago. and the suppository formulation of diclofenac sodium by simultaneous data fitting using NONMEM. 2003. Guidance for Industry. ACKNOWLEDGMENTS The authors wish to thank the staff pharmacists. Address correspondence to: Isam I.I. http://www. fda.I. and technicians at IPRC for their help and cooperation. 55th ed. Amidon GL. Acta Pharmaceutica Sciencia.gov/downloads/Drugs/Guidance ComplianceRegulator yInformation/Guidances/ UCM072137. The variability.com. Population pharmacokinetics of azithromycin after peroral administration to healthy volunteers.8 to 11 hours previously reported in other studies. Najib NM. Acta Pharmacol Sin. Mosby’s Drug Consult. REFERENCES 1.salem@iprc. 2. 2002–2007. Population Pharmacokinetics. 1998. Center for Drug Evaluation and Research. which was similar to the previously reported Tmax of 1. which was shorter than that observed in previous research. Determination of loratadine in human plasma by liquid chromatography electrospray ionization ion-trap tandem mass spectrometry. which again supports the choice of a 2-compartment model. The authors have indicated that they have no conflicts of interest regarding the content of this article. 7. 2009.pdf. This indicates acceptable datafitting and model choice. Center for Veterinary Medicine. 2001:2884–2885.65 hours. 2004.43:151–154. Chen XY. 10. Jordan. et al. Accessed January 14.24:715–718.fda. US Dept of Health and Human Services. Idkaidek NM. The t1/2 for loratadine ranged from 3. Smith DE. the population t1/2 for loratadine was found to be 3. London. Bioanalytical Method Validation. Weglein R. As shown in the table. Dong YM.
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