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Multiple-Dose Pharmacokinetics and Safety of Desloratadine in Subjects With Moderate Hepatic Impairment

From Schering-Plough Research Institute, Kenilworth, New Jersey (Dr Gupta, Dr Wang) and Schering-Plough Research Institute, Summit, New Jersey (Ms Kantesaria).

Address for correspondence: Samir K. Gupta, PhD, MBA, Schering-Plough Research Institute, K15-22745, 2015 Galloping Hill Road, Kenilworth, NJ 07033.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Desloratadine, a nonsedating histamine H₁-receptor antagonist, is metabolized to 3-hydroxy (3-OH) desloratadine. Impaired hepatic function could result in increased exposure to desloratadine. This study assessed possible differences in the pharmacokinetics and safety of desloratadine and 3-OH desloratadine in subjects (N = 21) with moderate hepatic dysfunction or normal liver function. Subjects were given desloratadine 5 mg once daily for 10 days and were assessed in several pharmacokinetic parameters. A similar degree of plasma protein binding to desloratadine and 3-OH desloratadine was observed in healthy volunteers and subjects with moderate hepatic impairment. All subjects with hepatic impairment were normal metabolizers. Three subjects with normal liver function, all African American, were identified as poor metabolizers. Exposure to desloratadine in the poor metabolizers was 2.6- to 6.5-fold greater than in other subjects with normal liver function. Eleven treatment-related adverse events, all mild to moderate in severity, were reported. Results suggest that subjects with moderate hepatic impairment experienced a greater increase in desloratadine exposure than subjects with normal liver function. Poor metabolizers had more exposure to desloratadine than normal metabolizers with or without hepatic impairment. Desloratadine administered at a daily dose of 5 mg was well tolerated.

Key Words: Desloratadine • pharmacokinetics • hepatic impairment

A previous single-dose study compared the pharmacokinetics and safety of desloratadine in subjects with mild, moderate, and severe hepatic impairment with those in subjects with normal liver function. No statistically significant differences in maximum observed plasma concentration (C_max) and AUC were observed between the hepatic dysfunction groups. However, systemic exposure (as assessed by C_max and AUC) to desloratadine and 3-OH desloratadine was almost twice as high in subjects with hepatic dysfunction than in subjects with normal liver function (unpublished data, Schering Corporation). Because the half-life of desloratadine was prolonged in patients with hepatic impairment, a higher degree of accumulation is expected in this group.

It is important to evaluate the exposure of desloratadine and assess the safety and tolerability following repeated treatment. The purpose of this study was to assess possible differences in the pharmacokinetics and safety of desloratadine and its metabolite in patients with moderate hepatic dysfunction and healthy subjects following 5-mg once-daily dosing for 10 days.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Prior to study initiation at the 2 centers, the study protocol and the informed consent forms were reviewed and approved by their respective institutional review boards (IRB): site 1, Clinical Research Center, IRB, New Orleans, Louisiana; site 2, Clinical Pharmacology Associates, Southern Institutional Review Board Inc, Miami, Florida. A total of 21 adult subjects—12 with moderate hepatic impairment (group 1) and 9 with normal hepatic function (group 2)—were enrolled. Subjects in group 2 were age-, height-, and weight-matched, where possible, to those in group 1.

Inclusion criteria dictated that participants eligible for study entry be 18 to 65 years of age, with clinical laboratory tests (complete blood count [CBC], blood chemistries, urinalysis) within normal limits or clinically acceptable to the investigator/sponsor (other than laboratory tests expected to be out of the reference-group range for group 1). Participants also were required to have a negative urine drug screen for drugs with a high potential for abuse and a physical examination and electrocardiogram (ECG) (12-lead recorded at 25 mm/s and reporting ventricular rate and PR, QRS, QT, and QTc intervals) within normal limits or clinically acceptable to the investigator/sponsor. Subjects in group 1 had chronic liver disease 1 year (confirmed by biopsy or imaging techniques; extent of disease defined by Pugh's modification of Child's classification of severity of liver disease) and no significant medical conditions unrelated to their hepatic disorder. Subjects in group 2 had no clinically significant diseases or conditions that would require a physician's care or interfere with study evaluations or procedures. Subjects were only included if they had submitted written informed consent prior to study enrollment and adhered to restrictions and examination schedules.

Participants were excluded if they had a history of any clinically significant local or systemic infectious diseases within 4 weeks prior to initial treatment administration, had used alcohol within 72 hours prior to administration of study drug, had participated in other clinical trials or used an investigational drug within 30 days prior to study entry, had a clinically significant history of food or drug allergy, had a positive serum/urine pregnancy test at screening or on admission (females), had a portacaval shunt implanted, had primary biliary cirrhosis or any form of cholestatic disease, or had used drugs with a long half-life (eg, astemizole) within 30 days of drug administration (day 1). Exclusion from group 1 was attributable to noncompliance with a stable treatment regimen for hepatic disease for 7 days prior to dosing, the use of medications known to induce hepatic enzymes (ie, rifampicin) within 30 days of dosing (day 1), the use of medications known to inhibit hepatic enzymes within 48 hours prior to dosing (day 1), or the presence of chronic liver disease with circulating HIV antibodies. Exclusion from group 2 was attributable to the use of any drugs (except acetaminophen within 72 hours) within 2 weeks prior to study, the presence of circulating HIV or hepatitis C antibodies, or the presence of hepatitis B surface antigens.

Study Design
This was a phase I, open-label, multicenter, multiple-dose, parallel-group study. Subjects were administered desloratadine 5 mg orally once daily in the morning on days 1 through 10. On day 10, each subject received a desloratadine tablet following an overnight fast. Physical examinations were performed prior to and at the end of the study (120 hours postdose, on day 15). A medical history was obtained at screening. Blood chemistries, hematology, ECGs, and urinalyses were performed at screening, before treatment administration, and 120 hours after the last dose. Subjects were continuously observed and were questioned for the possible occurrence of adverse events (AEs). Prior and concomitant medications were recorded on case report forms. No medications (investigational, prescription, or over-the-counter) were permitted in group 2 without prior approval from the principal investigator and sponsor, except in the case of a medical emergency. Subjects in group 1 were maintained on their established medications.

All doses were administered at the participating study centers under the supervision of site personnel. Compliance with dosing was ensured by monitoring the administration of the study drug. Compliance with study procedures was ensured by confinement of subjects from day -1 through 120 hours after the last dose (day 15).

Blood Sampling and Bioanalytical Analyses
The primary objective of this study was to compare the pharmacokinetics of desloratadine and 3-OH desloratadine in subjects with hepatic impairment versus subjects with normal liver function. Blood samples (approximately 5 mL) were collected predose on day -2 and before drug administration on days 1, 8, and 9. On day 10, serial blood samples were collected at the following time points: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours postdose. Blood samples were collected in heparinized tubes and centrifuged for 15 minutes at approximately 4°C and 1500g. Plasma was separated and frozen to at least -20°C and shipped frozen with dry ice to the analytical laboratory (PPD Pharmaco, Richmond, Virginia). Plasma samples were then assayed for desloratadine and 3-OH desloratadine concentrations, using validated liquid chromatography with tandem mass spectrometric detection.⁸ The internal standards for desloratadine and 3-OH desloratadine were d₄-desloratadine and d₄-3-OH desloratadine, respectively.

The lower limit of quantitation (LLOQ) was 0.025 ng/mL for both desloratadine and 3-OH desloratadine. The accuracy (% bias) at the LLOQ was 5.27 and 9.31 for desloratadine and 3-OH desloratadine, respectively. The precision coefficient of variation (%CV) for samples at the LLOQ was 2.96 and 4.73 for desloratadine and 3-OH desloratadine, respectively. For desloratadine, the between-run %CV was 7.5, 3.5, and 2.4 for low, medium, and high quality control (QC) concentrations, respectively. For 3-OH desloratadine, the between-run %CV was 6.3, 3.9, and 3.2 for low, medium, and high QC concentrations, respectively. All values below the lower limit of quantification were reported as zero.

Protein Binding
The plasma protein binding (PB) of desloratadine and 3-OH desloratadine was determined for each subject by an ultrafiltration technique (Centrifree Micropartition Device, Millipore Corp, Bedford, Massachusetts) using pooled plasma from samples collected at several time points (from 0.5 to 6 hours) postdose. The PB was determined by the ultrafiltration method and was calculated as follows:

where C_p is the concentration in plasma and C_u is the concentration in the corresponding ultrafiltrate.

Pharmacokinetic Analysis
The plasma concentration-time data for desloratadine and 3-OH desloratadine were subjected to pharmacokinetic analysis by noncompartmental methods using the WinNonlin® Professional computer program (version 3.2; Pharsight Corp, Mountain View, California).

For each subject, the following pharmacokinetic parameters were determined as appropriate for desloratadine and 3-OH desloratadine: C_max, time of maximum plasma concentration (t_max), minimum plasma concentrations (C_min) predose days 8 to 10, AUC, apparent total body clearance at steady state (CL/Fss), body weight-adjusted apparent volume of distribution (Vd/F), and terminal phase half-life (t).

The terminal phase rate constant (K) was calculated as the negative of the slope of the log-linear terminal portion of the plasma concentration-time curve using linear regression. The t was calculated as 0.693/K. The AUC from time 0 to 24 hours (AUC_(0-24h)) was calculated using the trapezoidal method. The CL/Fss was determined as follows:

Vd/F (body weight adjusted) was determined as follows:

The metabolite-to-parent AUC ratio was calculated as follows:

Statistical Methods
Log-transformed C_max and AUCs were statistically analyzed using an analysis of variance (ANOVA) model. The effect of liver function impairment was extracted. Ninety percent confidence intervals (90% CI) for the mean difference between groups and the power to detect a 20% difference at a P value of .05 were calculated using the pooled residual error and associated degrees of freedom from the ANOVA. In addition, to determine whether steady-state conditions were reached, trough concentrations (C_min) for days 8 to 10 were analyzed for each group of subjects using an ANOVA model, extracting effects attributable to subject and day.

Safety Assessments
The secondary objective of the study was to determine the safety and tolerability of multiple-dose administration of desloratadine in subjects with moderate hepatic impairment. Safety was assessed by monitoring AEs, laboratory safety tests (CBC, blood chemistries, and urinalysis), physical examinations, vital signs, and ECGs. The intensity (severity) of AEs was assessed according to the Common Toxicity Criteria (CTC) grading system. For AEs not covered by the CTC grading system, the following definitions were used:

Mild: awareness of sign or symptom

Moderate: discomfort sufficient to cause interference with usual activity or to affect clinical status

Severe: incapacitating, with inability to do usual activity; may significantly affect clinical status

Life-threatening: presents a definite hazard, with potential for causing death

A serious AE was any event that was fatal, was life-threatening (ie, subject was at immediate risk of death from the AE as it occurred), was significantly or permanently disabling, required in-patient hospitalization or prolonged hospitalization, or was a congenital anomaly or birth defect.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
All 21 enrolled subjects completed the study and were included in the pharmacokinetics and safety analyses. Subjects who participated in the study had normal hepatic function (n = 9) or moderate hepatic impairment (n = 12), were aged 40 to 66 years, and weighed between 53 and 109 kg. All subjects received their assigned treatment, because all doses were administered at the study center under the supervision of study personnel. The presence of desloratadine and 3-OH desloratadine in plasma samples confirmed that all subjects received treatment.

Pharmacokinetics
Steady-state conditions of desloratadine and 3-OH desloratadine for days 8 to 10 were assessed by an ANOVA model using C_min values. No statistically significant differences were identified for within-group comparisons, indicating that the pharmacokinetics were evaluated on day 10 under steady-state conditions. At day 10, the %CV C_min values for desloratadine were 53% for group 1 and 100% for group 2; for 3-OH desloratadine, they were 43% and 81%, respectively. C_max %CV values for desloratadine were 46% and 66% for groups 1 and 2, respectively, and 51% and 78% for 3-OH desloratadine. The respective %CV values for AUC_(0-24h) were 43% and 82% for desloratadine and 43% and 78% for 3-OH desloratadine.

The effect of hepatic dysfunction on C_max and AUC was assessed using the log-transformed parameters. The results of statistical analysis based on log-transformed pharmacokinetic parameters revealed no statistically significant differences (P > .1) between healthy volunteers and patients with moderate renal impairment, attributable to large inter-subject variability. A similar degree of plasma protein binding to desloratadine and 3-OH desloratadine was observed in both healthy volunteers and subjects with moderate hepatic impairment.

The AUC ratio of 3-OH desloratadine to desloratadine can be used to distinguish poor metabolizers from normal metabolizers. A ratio of <10% is the criterion used to identify poor metabolizers. Applying this criterion to subjects with normal liver function resulted in the identification of 3 subjects (all African American) as poor metabolizers. The exposure to desloratadine in these subjects (AUC_(0-24h) = 195-282 ng·h/mL; mean 240 ng·h/mL) was 2.6- to 6.5-fold greater than that in other normal subjects (AUC_(0-24h) = 30-108 ng·h/mL; mean 58.0 ng·h/mL). Correspondingly, the exposure to 3-OH desloratadine in these subjects was much lower than that in the other volunteers. Both liver impairment and poor metabolism would lead to a decreased AUC (3-OH desloratadine/desloratadine) ratio, making it impossible to distinguish a poor metabolizer attributable to hepatic dysfunction from a true poor metabolizer.

Based on the data submitted to support the registration of desloratadine, the trait of poor metabolism appears to be expressed at a higher frequency in subjects of African descent (20%) compared with Caucasians (2.7%). The presence of 3 poor metabolizers (all African American) within the normal liver function group confounded the assessment of liver impairment on desloratadine pharmacokinetics. (All Caucasian subjects were found to be normal metabolizers.) Thus, the pharmacokinetic data were also analyzed following stratification of the data within the normal and hepatic dysfunction groups by race. The objective was to reduce the variability imparted by the poor metabolizers (see Table I). The results of the analysis by race are illustrated in Figure 1 and in Tables II and III.

View larger version (40K): [in this window] [in a new window]   Figure 1. Comparisons of mean plasma concentration-time profiles of desloratadine and 3-OH desloratadine between African American and Caucasian subjects with moderate hepatic impairment and normal liver function.

The mean half-life (34.1 hours) of desloratadine in normal metabolizers with normal liver function is similar to that observed in the earlier study in normal metabolizers. The median desloratadine AUC value in normal metabolizers with hepatic impairment was approximately 3-fold greater than that in normal metabolizers with normal liver function (112 vs 40.3 ng·h/mL), consistent with data reported previously.

Overall, the results suggest that subjects with moderate hepatic impairment who are normal metabolizers may experience a 3-fold increase in desloratadine exposure (AUC). The data suggest that poor metabolizers had a greater exposure to desloratadine than normal metabolizers with or without hepatic impairment, regardless of racial group.

Safety
Five healthy subjects (56%) and 6 subjects with moderate hepatic impairment (50%) reported at least 1 treatment-emergent AE. In healthy subjects, headache was the most commonly reported AE (4/9, 44%). In subjects with moderate hepatic impairment, headache and drowsiness were the most commonly reported AEs (2/12, 17%). All AEs were mild to moderate in severity. No subject discontinued the study because of an AE. No serious AEs were reported in this study, nor were any clinically significant changes in ECG readings or vital signs noted.

Subjects with moderate liver impairment had findings consistent with underlying chronic liver disease, including anemia, decreased platelet counts, and nonclinically significant changes in white blood cell count differential. Various abnormally high and low laboratory values were noted; none were clinically significant. One subject with moderate hepatic impairment had elevated -glutamyl transferase (35 U/L at baseline, 66 U/L on day 15) and serum glutamic pyruvic transaminase (22 U/L at baseline, 49 U/L on day 15).

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Hepatic impairment can considerably change how a drug is metabolized. This altered metabolism can lead to increased exposure, leading to drug toxicity. Desloratadine is metabolized to 3-OH desloratadine; therefore, results from a study such as this, which enrolled normal subjects as well as those with hepatic impairment, can provide useful information to physicians who are considering prescribing desloratadine to patients who may have hepatic disease.

Results from this study showed that desloratadine administered at a daily dose of 5 mg was well tolerated in subjects with moderate hepatic impairment. Three of the 4 African American subjects with normal hepatic function were also poor metabolizers, which led to an increase in the overall AUC in this group. Such an increase in AUC would not usually be found in those with normal liver function.

An increase in AUC and C_max was noted in patients with moderate hepatic impairment; this was consistent with single-dose findings.⁶ When the data for the Caucasian subjects were analyzed, thereby eliminating confounding factors such as race and metabolizer status, the median exposure to desloratadine in subjects with moderate hepatic impairment was approximately 3-fold greater than that in subjects with normal hepatic function. Subjects with moderate hepatic impairment and normal metabolizers with normal liver function showed similar exposure to 3-OH desloratadine, the major active metabolite of desloratadine. Steady state was achieved in both the normal liver function and the hepatic impairment populations. However, the 3 poor metabolizers did not appear to reach steady state at day 10. This is consistent with a study of desloratadine given at 9 times the recommended dose (45 mg/d) for 10 days, where the 5 subjects who were poor metabolizers did not achieve steady state (although there were no safety issues, including electrocardiographic effects, with regarding the increased exposure to desloratadine⁹).

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Financial disclosure: None declared.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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5. Barecki ME, Casciano CN, Johnson WW, Clement RP. In vitro characterization of the inhibition profile of loratadine, desloratadine, and 3-OH-desloratadine for five human cytochrome P450 enzymes. Drug Metab Dispos. 2001;29: 1173-1175.[Abstract/Free Full Text]

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7. Khalileh S, Lutsky B, Lorber R. Safety of desloratadine in poor metabolizers. Paper presented at: American College of Allergy, Asthma & Immunology 2004 Annual Meeting; November 12-17, 2004; Boston, Mass.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Gupta, S. K. Articles by Wang, Z. Search for Related Content PubMed PubMed Citation Articles by Gupta, S. K. Articles by Wang, Z. Social Bookmarking                   What's this?