British Journal of Dermatology
T H E R A P E U T I CS
The single-dose pharmacokinetics of alitretinoin and its metabolites are not significantly altered in patients with cirrhosis J.P. Thyssen,1 L. Vester,1 C. Grønhøj Larsen,2 K. Smidt,3 P. Jakobsen,3 S.H. Hansen,4 D. Vind-Kezunovic,1 L.L. Gluud5 and F. Grønhøj Larsen6 1
Department of Dermato-allergology, Copenhagen University Hospital Gentofte, Hellerup, Denmark Department of Otolaryngology, Head and Neck Surgery, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark 3 Department of Biomedicine-Pharmacology, Aarhus University, Aarhus, Denmark 4 Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark 5 Department of Internal Medicine, Copenhagen University Hospital Gentofte, Hellerup, Denmark 6 Taastrup Dermatology Clinic, Taastrup, Denmark 2
Summary Correspondence Frederik Grønhøj Larsen. E-mail: [email protected]
Accepted for publication 22 July 2013
Funding sources The study was supported by an independent research grant from the Aage Bangs Foundation and the Steenbecks Foundation.
Conflicts of interest None declared. DOI 10.1111/bjd.12546
Background Alitretinoin (9-cis-retinoic acid, Toctinoâ) has been marketed recently for oral therapy for chronic hyperkeratotic hand eczema. As alitretinoin is highly lipophilic and metabolized mainly in the liver, it is currently considered to be contraindicated in patients with liver disease. However, the pharmacokinetics and metabolism of alitretinoin have not been studied in these patients. Objectives To study the single-dose pharmacokinetics and metabolism of alitretinoin and its metabolites in patients with cirrhosis following oral administration. Methods Eight patients with cirrhosis and eight matched volunteer healthy controls were given a single 30-mg oral dose of alitretinoin. Blood and urine samples were collected during the following 24-h study period. Samples were analysed for alitretinoin and for known metabolites using reverse-phase high-performance liquid chromatography. The pharmacokinetics were then evaluated using standard noncompartmental models. Results No significant differences were found between healthy controls and patients with cirrhosis when analysing the pharmacokinetic parameters of alitretinoin and its metabolites. Thus, the mean half-lives of alitretinoin were 53 and 56 h (P = 0.733) and the oral clearances were 192 and 139 L h 1 kg 1 (P = 0243) in the patient group and the healthy control group, respectively. Conclusions The metabolism and pharmacokinetics of alitretinoin following oral administration of the recommended dose of 30 mg for the treatment of severe hand eczema were similar in patients with cirrhosis and in healthy controls. If indicated, alitretinoin can be used in these patients with careful and close monitoring.
What’s already known about this topic?
Alitretinoin is prescribed for oral therapy for chronic hyperkeratotic hand eczema. It is contraindicated in patients with liver disease, although its pharmacokinetics and metabolism have not been studied in these patients.
What does this study add?
No significant differences were found between healthy controls and patients with cirrhosis in the pharmacokinetics of alitretinoin and its metabolites. Oral alitretinoin can be used for such patients with careful and close monitoring.
British Journal of Dermatology (2014) 170, pp408–414
© 2013 British Association of Dermatologists
Single-dose pharmacokinetics of alitretinoin, J.P. Thyssen et al. 409
Oral therapy with the retinoid alitretinoin [9-cis-retinoic acid (9-cis-RA), Toctinoâ (Stiefel, Uxbridge, U.K.)] is sometimes indicated for the treatment of chronic hyperkeratotic hand eczema, typically in severe cases.1 Retinoids are characterized by being lipophilic and strongly bound to plasma lipoproteins.2 Metabolism typically begins in the gastrointestinal tract, but takes place predominantly in the liver.3,4 It is estimated that renal excretion of metabolites constitutes only 10–15% of the total dose administered.5 The pharmacokinetics of singledose-administration alitretinoin have been studied in animals6 and in healthy men,7 and multiple-dose administration has been evaluated in patients with moderate-to-severe hand eczema.8 Based on these studies, the terminal half-life ranges from 2 to 10 h and the pharmacokinetics appear to be linear. However, there seems to be large interindividual variability in the pharmacokinetic parameters. Alitretinoin metabolism involves isomerization and oxidation to 4-oxo-RA-metabolites (Fig. 1). A metabolic study on plasma, urine and faeces collected from healthy young men showed that after 28 days of treatment with alitretinoin (20 mg daily), a mixture of 4-oxo-RA isomers was found, with 4-oxo-9-cis-RA (163 53 ng mL 1) being the main metabolite. The concentration of other possible metabolites (13-cis-RA and all-trans-RA) was near the limit of detection, but evidently present. Moreover, in blank plasma samples, 4-oxo-RA isomers, mainly 4-oxo-13-cis-RA, 13-cis- and alltrans-RA were detected.9 At present, the use of alitretinoin is considered to be contraindicated in patients with liver disease because the metabolism and pharmacokinetics of alitretinoin in these patients have not yet been studied. We compared the single-dose pharmacokinetics of alitretinoin and its metabolites in patients with cirrhosis with those of healthy controls.
Patients and methods Study population Eight volunteers (four male and four female, age > 18 years) with cirrhosis and Child–Pugh grade A or B (rating of ascites, encephalopathy, serum bilirubin levels and prothrombin
time),10 as well as eight sex-, age- ( 5 years), height- and weight-matched ( 15%) volunteers were enrolled in the study (Table 1). All patients had chronic liver disease that was stable for at least 1 month, ongoing or previous signs of hepatic decompensation and clinical, as well as histological, signs of cirrhosis. Urine samples from female participants were screened for pregnancy prior to study enrolment, and reliable contraceptive use in female study participants was required for at least 1 month after the study ended. Exclusion criteria included pregnancy or lactation, encephalopathy (> grade II) or neurological disease, psychiatric disorders, cancer, cardiac disease or myocardial infarction within the past 12 months, renal dysfunction, severe refractory ascites, ongoing bleeding from oesophageal varices, HIV infection or participation in other clinical trials. Controls were healthy volunteers who had no renal, haematological or hepatic abnormalities upon blood screening. Study design An investigator-initiated, open-label, single-dose pharmacokinetic study was conducted in accordance with the European guidelines on good clinical practice and the revised Declaration of Helsinki. Approval from the local ethics committee was obtained (Protocol H-4-2010-073). Written informed consent was obtained from participants before the study began. The study was registered on www.clinicaltrials.gov Table 1 Demographic details of participants
Number of participants Male/female Age (years) mean (SD) Range Weight (kg) mean (SD) Range Height (cm) mean (SD) Range
Patients with cirrhosis
8 4/4 586 (97) 45–73 792 (215) 586–1127 175 (8) 163–186
8 4/4 589 (92) 45-69 860 (215) 570–1100 175 (6) 169–187
Fig 1. Structural formulas of alitretinoin [9cis-retinoic acid (RA)] and its metabolites. © 2013 British Association of Dermatologists
British Journal of Dermatology (2014) 170, pp408–414
410 Single-dose pharmacokinetics of alitretinoin, J.P. Thyssen et al.
(NCT01261923). Fifty 10-mg capsules of alitretinoin (Toctinoâ) were purchased from a local pharmacy. At the hospital in the morning, each participant was given three capsules to be taken together providing a total dose of 30 mg. All participants were given the same standard breakfast meal together with the medication, as absorption of retinoids is increased when administered with food.11,12 While no further foods were allowed during the next 4 h, there were no restrictions on food intake afterwards. Prior to alitretinoin administration, and before food intake, a venous predose blood sample was collected. After drug administration, blood samples were drawn at the following time points: 025, 05, 075, 1, 125, 15, 175, 2, 25, 3, 35, 4, 5, 6, 8, 12 and 24 h. The blood samples (8 mL) were collected in aluminium-wrapped amber glass tubes, as retinoids are very sensitive to light exposure. The samples were centrifuged immediately (10 min, 1580 g), and then plasma was separated and kept carefully protected from exposure to ambient light at 20 °C until analysis. Urine samples were collected prior to drug administration and at the following time intervals: 0–2, 2–6, 6–12 and 12–24 h. The urine volumes were measured and 10-mL samples were protected from light at 20 °C until analysis. Bioanalysis Quantification of alitretinoin and its main metabolites (4oxo-9-cis-RA, 13-cis-RA, 4-oxo-13-cis-RA, all-trans-RA and 4oxo-all-trans-RA) in plasma was performed in a blinded manner by Inovalab AG, Kaegenstrasse 17, Reinach, Switzerland, using a validated column-switching high-performance liquid chromatography (HPLC) system consisting of an autosampler (AS4000; Hitachi, Tokyo, Japan) connected to a trapping column (Inertsil ODS-3, 5 lm, 5 9 46 mm; GL Sciences, Torrance, CA, U.S.A.), an analytical column (Inertsil ODS, 5 lm, 21 9 250 mm, two columns coupled; GL Sciences) and an ultraviolet detector (Thermo Finnigan UV6000LP; Thermo Electron Corporation, San Jose, CA, U.S.A) for detection of alitretinoin (9-cis-RA) and its main metabolites at a wavelength of 360 nm. Calibration samples (range of 1– 100 ng mL 1) were prepared in ethanol, and quality control samples covering the calibration range were prepared in human plasma. The method was specific for all six compounds, and no significant interference with blank human plasma samples was detected. The day-to-day performance was controlled by the analysis of quality control samples. The work-up of samples (450 lL of human plasma) was carried out by protein precipitation with 1350 lL of ethanol containing acitretin as the internal standard. After vortexing, the sample was centrifuged at 4 °C for at least 10 min. An aliquot (1500 lL) of each supernatant was then injected onto the trapping column. From 00 to 50 min the mobile phases of the HPLC pumps 2 and 3 were directed to the waste, which included the relatively large injection volume. After washing the trapping column, the analytes were eluted onto the analytical column and chromatographed. The mobile phase used was a combination of acetonitrile and British Journal of Dermatology (2014) 170, pp408–414
ammonium acetate buffer. Recoveries for alitretinoin and metabolites were ≥ 913%. Quality control and unknown samples were subjected to the same assay procedure. The lower limit of quantification was the lowest concentration of the analytes in an unknown plasma sample that could be quantitatively determined with acceptable accuracy and precision (relative SD < 20%). This limit was set to 1 ng mL 1 for all six analytes. Quantification of alitretinoin and its metabolites in human urine was performed in a blinded manner by Basilea Pharmaceutica, Basle, Switzerland using a newly developed HPLC tandem mass spectrometry (HPLCMS/MS) assay. The method was validated for alitretinoin, 13-cis-RA, all-trans-RA, 4-oxo-9-cis-RA, 4-oxo-13-cis-RA and 4-oxo-all-trans-RA in the range 1–10 ng mL 1. The interassay accuracy ranged from 919% to 107% for all analytes, while the interassay precision ranged from 25% to 74%. All urine samples were analysed together with the limit of quantification (1 ng mL 1) samples of all analytes and only those samples that showed an area ≥ 50% of the matched limit of quantification sample were quantified in a second run. Therefore 100 lL urine was quenched with 100 lL ethanol containing 500 ng mL 1 deuterium-labelled internal standards (alitretinoin-D8 and 4-oxo-9-cis-RA-D10). Samples were centrifuged and an aliquot of 10 lL of each supernatant was then injected into the HPLC-MS/MS using an electrospray ionization interface and multiple reaction monitoring. A guard column (Targa C18, 3 lm, 20 9 21 mm; Chrom Tech, Apple Valley, MN, U.S.A.) and an analytical column (Stability Amid C12, 3 lm, 100 9 2 mm; Altmann Analytik, Munich, Germany) were used for separation using 10 mmol L 1 ammonium acetate and methanol over a 22-min gradient (56% methanol for 10 min, 62% for 10 min, 99% for 2 min; flow 025 mL min 1). Using a negative polarity detection mode, the parent-to-daughter ion transition for alitretinoin, 13-cisRA and all-trans-RA was 299–255 (m/z); for alitretinoin-D8 308–264 (m/z); for 4-oxo-9-cis-RA, 4-oxo-13-cis-RA and 4oxo-all-trans-RA 313–269 (m/z) and for 4-oxo-9-cis-RA-D10 323–279 (m/z). Pharmacokinetic analysis Pharmacokinetic parameters for the parent drug were calculated for each study participant using standard noncompartmental methods. The maximum plasma concentration (Cmax) and the time of its occurrence (tmax) were obtained directly from the concentration–time data on alitretinoin and its metabolites. The area under the curve (AUC0–last) was calculated using the linear trapezoidal method up to the last measured concentration. AUCinf (the area under the curve from time 0 to time infinity) was not calculated given that alitretinoin and its metabolites are endogenous compounds that never reach zero in the plasma. The terminal elimination half-life (t½) was calculated as ln(2)/kz, where kz is the terminal elimination rate constant of alitretinoin. Apparent clearance after oral administration, Cl/F (weight normalized), was calculated © 2013 British Association of Dermatologists
Single-dose pharmacokinetics of alitretinoin, J.P. Thyssen et al. 411
as: Cl/F = Dose/AUClast, where F = bioavailability. Cmax, tmax and AUClast were calculated for each detected metabolite. Statistical analysis The values for Cmax, AUC and Cl/F were logarithmically transformed prior to the analyses. Point estimates and 95% confidence intervals (CIs) for the difference between the cirrhosis group and the control group were constructed. The point estimates and CIs on the log-scale were back-transformed to give estimates for ratio comparison between the two study groups. A nonparametric method (Wilcoxon signed-rank test) was used to analyse tmax. The ratio of the sum of metabolite-AUCs to that of the parent drug in the two treatment groups was also evaluated statistically. Pharmacokinetic calculations and statistical evaluations were performed using GraphPad Prism Version 5 (La Jolla, CA, U.S.A.) and MedCalc Version 12.4.0 (MedCalc Software, Mariakerke, Belgium).
therefore estimated from the mean plasma concentrations from each of the two study groups. The terminal part of the plasma concentrations time profile (6–24 h) was fitted to a monoexponential decay function by a weighted non linear regression analysis (weight factor: the reciprocal of the concentration). The best fit exponential decay curves for the two subject groups are shown in Figure 3. The mean half-lives were 53 h for the patients and 56 h for the controls (P = 0.733). The calculated pharmacokinetic parameters following oral administration of 30 mg alitretinoin in the two treatment groups showed no significant differences (Table 3). While trace amounts of possible metabolites – 13-cis-RA, all-transRA, and 4-oxo-9-cis-RA – were found in predose samples from the majority of study subjects, 4-oxo-13-cis-RA was not found at all (Table 2). However, 4-oxo-all-trans-RA was found in nearly all subjects. Individual plasma concentration–time plots showed an increase followed by a decrease,
Results Patients and controls Demographic details of the two treatment groups are provided in Table 1. No significant differences between the two groups with respect to age, sex, weight or height were observed. Pharmacokinetic results Predose plasma concentrations of alitretinoin were below the limit of quantification (1 ng mL 1) in all subjects in the two groups (Table 2). Twenty-four hours after oral administration of 30 mg of alitretinoin, nearly all the parent drug was cleared from the plasma in both groups. The mean serum alitretinoin concentrations were stratified by time curves in patients with cirrhosis and in healthy controls (Fig. 2). As four subjects in the control group and five subjects in the patient group had plasma concentrations below the limit of quantification after 24 h, it was not possible to obtain reliable terminal half-lives from the individual subjects. The mean terminal elimination rate constant kz was
Fig 2. Log plasma concentration–time profiles after oral administration of 30 mg of alitretinoin (Toctinoâ) to patients with cirrhosis (dotted line, ○) and to healthy controls (solid line, ■).
Table 2 Predose plasma concentrations (ng mL 1) of alitretinoin and its metabolites in the two subject groups
Alitretinoin 13-cis-RA All trans-RA 4-oxo-all-trans-RA 4-oxo-9-cis-RA 4-oxo-13-cis-RA
Cirrhosis mean ( SD)
Healthy controls mean ( SD)
BLQ 15 (001) 15 (02) 80 (94) 29 (10) BLQ
BLQ 16 (02) 13 (03) 53 (50) 25 (06) BLQ
RA, retinoic acid; BLQ, below limit of quantification (1 ng mL 1).
© 2013 British Association of Dermatologists
Fig 3. Plasma concentration–time profile (6–24 h) fitted by weighted nonlinear regression to monoexponential decay functions following a single exposure to 30 mg of alitretinoin (Toctinoâ) in patients (dotted line, ○) and healthy controls (solid line, ■). British Journal of Dermatology (2014) 170, pp408–414
412 Single-dose pharmacokinetics of alitretinoin, J.P. Thyssen et al. Table 3 Comparison of alitretinoin (Toctinoâ) single dose pharmacokinetic parameters between patients with cirrhosis and matched healthy controls
Parameter 1 a
Cmax (ng mL ) AUC0–last (ng h mL 1)a tmax (h)b t½ (h) Cl/F (L h 1 kg 1)a
Cirrhosis (n = 8), mean ( SD)
Healthy controls (n = 8), mean ( SD)
Estimated geometric mean ratio (patients/ controls)
101 248 103 53 192
144 314 084 56 139
(40) (116) (05–125) (05)c (098)
(40) (86) (05–10) (07)c (086)
Estimated mean difference
015 030 142
P-value 0098 0205 0095 0733 0243
95% confidence interval 041–110 044–124 22 16 074–154
Cmax, maximum plasma concentration; AUC, area under the curve; tmax; time of occurrence of Cmax; t½, terminal elimination half-life; Cl/F, weight-normalized oral clearance. aArithmetic mean; bmedian and range; c (SEM).
suggesting that the compound appeared as a metabolite. Kinetic data after subtraction of predose concentrations for the detected metabolites are presented in Table 4. The main metabolite of alitretinoin in plasma appeared to be 4-oxo-9cis-RA. The tendency towards a lower AUC of the parent compound and the main metabolite 4-oxo-9-cis-RA in patients compared with healthy controls is mainly due to a low bioavailability in one of the patients. Statistically significant differences of minor importance were observed with respect to Cmax for 13-cis-RA (P = 0045) and Cmax for the main metabolite 4-oxo-9-cis-RA (P = 0048). In urine, only small amounts of unconjugated parent compound and of unconjugated 4-oxo-9-cis-RA, (≤ 01% of administered dose) were identified (Table 5).
Discussion Alitretinoin is used for the treatment of chronic hyperkeratotic hand eczema and is currently contraindicated in patients with liver disease as the drug is mainly hepatically metabolized. As therapy with alitretinoin is sometimes warranted in such patients, the pharmacokinetics of the parent drug and its metabolites are worth exploring. Moreover, other systemic drugs such as methotrexate and azathioprine that can be used for the treatment of severe chronic hand eczema may have direct toxic effects on the liver, hence their use in patients with liver disease is limited. The present study showed no differences in the single-dose pharmacokinetics of alitretinoin 30 mg and its metabolites in patients with chronic stable liver
Table 4 Comparison of pharmacokinetic data of metabolites of alitretinoin (Toctinoâ) between patients with cirrhosis and matched healthy controls
Cirrhosis (n = 8) mean ( SD) 13-cis-RA AUC (ng h mL 1) AUCmetabolite/AUCparent (%) Cmax (ng mL 1) tmax (h)a All-trans-RA AUC (ng h mL 1) AUCmetabolite/AUCparent (%) Cmax (ng mL 1) tmax (h)a 4-oxo-all-trans-RA AUC (ng h mL 1) AUCmetabolite/AUCparent (%) Cmax (ng mL 1) tmax (h)a 4-oxo-9-cis-RA AUC, ng h mL 1 AUCmetabolite/AUCparent, % Cmax, ng mL 1 tmax, ha
772 (1103) 311 229 (090) 0875 (05–125) 1055 (612) 425 632 (251) 1 (05–125) 542 (324) 219 63 (48) 4 (10–12) 1620 (818) 653 299 (203) 125 (075–35)
Healthy subjects (n = 8) mean ( SD)
Estimated geometric mean ratio (patients/ healthy)
95% confidence interval
1897 (1690) 605 345 (107) 1 (075–2)
1887 (1434) 601 850 (291) 1125 (05–2) 740 (95) 236 58 (53) 125 (10–60) 2192 (485) 698 559 (252) 125 (10–15)
RA, retinoic acid; AUC, area under the curve; Cmax, maximum plasma concentration; tmax, time of occurrence of Cmax. aMedian and range.
British Journal of Dermatology (2014) 170, pp408–414
© 2013 British Association of Dermatologists
Single-dose pharmacokinetics of alitretinoin, J.P. Thyssen et al. 413 Table 5 Total amount (ng) of unconjugated parent drug (alitretinoin, Toctinoâ) and metabolites found in the urine of patients with cirrhosis and matched healthy controls. Urine samples (total volume) were collected for a period of 24 h. The other metabolites retinoic acid (RA), all-trans-RA and 4-oxo-all-trans-RA showed concentrations BLQ (below level of quantification) Patient/control no. Patients with cirrhosis Alitretinoin (ng) 4-oxo-9-cis-RA (ng) Healthy controls Alitretinoin (ng) 4-oxo-9-cis-RA (ng)
1 BLQ 5160 9 BLQ 320
2 BLQ 367 10 BLQ BLQ
Mean (SD) 3 BLQ BLQ 11 BLQ BLQ
4 BLQ BLQ 12 BLQ BLQ
disease and healthy controls. Our findings are in line with a previous study showing that the retinoid, etretinate, which is typically used in the treatment of plaque psoriasis, had similar pharmacokinetics in patients with hepatic fibrosis or cirrhosis when compared to patients with psoriasis with normal liver function.13 Linear relationships between both AUC and Cmax vs. administered dose (5–150 mg) have previously been demonstrated in healthy men.7 Furthermore, such dose proportionality has been found in adults with advanced cancer [dose: 5–140 mg (m2) 1].14 According to these relationships, the dose in our study of 30 mg of alitretinoin should yield a Cmax of approximately 120 ng mL 1 and an AUC of 340 ng h mL 1, which is consistent with our results (Table 3). However, a Cmax of only 82 ng mL 1 and an AUC of 220 ng h mL 1 were observed after administration of 40 mg of alitretinoin together with a high-fat meal to overnight fasting healthy subjects.11 When patients with severe chronic hand eczema were treated with various doses of alitretinoin for up to 24 weeks, no accumulation or time-dependent changes in the disposition of alitretinoin or its major metabolite, 4-oxo-alitretinoin, were found.8 The same tendency was demonstrated in cancer patients but only after very high dosing [100–140 mg (m2) 1], and a similar reduction in the AUC of the major metabolite 4-oxo-9-cis-RA was observed.14 All previous studies have reported that the tmax is approximately 3–4 h. However, we found that tmax was 103 and 084 h for patients and healthy controls, respectively. Although we cannot explain the faster absorption time, we speculate that it could be due to the nature of the standard meal given to the subjects before drug administration as well as the fasting state of the participants. The main metabolic pathways for all endogenous retinoids, including alitretinoin, involve isomerization and oxidation. Alitretinoin is preferentially metabolized by cytochrome (CYP) P450 2C8, CYP P450 2C9 and CYP P450 3A4 (CYP3A4). The effects of the CYP3A4 substrates, ketoconazole, simvastatin and ciclosporin A, have been studied with focus on drug interactions with alitretinoin.15,16 Neither simvastatin nor ciclosporin A affects the pharmacokinetics of alitretinoin. On the contrary, ketoconazole, a potent inhibitor of CYP3A4, significantly increases AUC and Cmax.15 In our study, none of the patients received ketoconazole but various other CYP substrates were © 2013 British Association of Dermatologists
5 BLQ 545 13 BLQ 371
6 255 1530 14 BLQ 1139
7 953 1539 15 875 2014
8 417 416 16 149 551
203 (342) 1195 (1712) 128 (306) 549 (705)
given. Thus, patients 1 and 3 (Table 5) were treated with simvastatin (inhibitor and stimulator of CYP3A4), patients 2, 3 and 6 with spironolactone (induces CYP3A4 expression and inhibits CYP2C8),17 patients 3 and 5 with esomeprazole and patient 7 with omeprazole (inhibits CYP3A4). Also, patient 5 received ciprofloxacin (inhibits CYP3A4)17 and patient 8 clopidogrel (inhibits CYP2C9) (University of Washington Drug Interaction Database http://www.druginteractioninfo.org/). Healthy volunteers were not medicated, but this difference in treatment proved not to be metabolically significant as we found no difference in AUC, clearance or terminal half-lives between the two groups. The half-life of the parent compound could not be determined in the individual subjects. Therefore, the mean half-life for each group is reported. No difference was found between the groups (53 h for patients and 56 h for healthy). These half-lives are in agreement with those reported in a previous study.8 Quite large interindividual differences were seen in both study groups for most of the pharmacokinetic parameters. This is not uncommon for retinoids and is probably explained by large differences in bioavailability. One patient showed unusually small plasma concentrations of the parent compound and its metabolites, which explains the tendency (not significant) towards smaller AUCs and lower Cmax in the patient group (Tables 3 and 4). The large oral clearance value found in this patient added to the rather large standard deviations. In conclusion, we found no significant differences in alitretinoin single dose pharmacokinetic parameters between patients with cirrhosis and healthy controls. Multiple-dose pharmacokinetic studies are needed before a change in the existing recommendations should be considered. If indicated, alitretinoin can be used in patients with liver disease but we recommend careful and close monitoring.
Acknowledgments Dr Jochen Spickermann is thanked for analysing the urine and plasma samples in a blinded manner.
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