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DRUG METABOLISM |
From the Divisions of Pulmonary, Allergy and Critical Care Medicine (Dr Sciurba) and Clinical Pharmacology (Dr Muindi, Dr Romkes, Dr Branch), University of Pittsburgh, Pittsburgh, Pennsylvania; University of California, Los Angeles (Dr Roth); Boston University, Boston, Massachusetts (Dr O'Connor); University of California, San Diego (Dr Ramsdell); Columbia University, New York, New York (Dr Schluger); Johns Hopkins University, Baltimore, Maryland (Dr Wise); and the Division of Biostatistics, University of Minnesota, Minneapolis (Dr Connett).
Address for reprints: Josephia R. Muindi, MD, PhD, Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Street, Buffalo, NY 14263; e-mail: josephia.muindi{at}roswellpark.org.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: ATRA • 13-cRA • plasma pharmacokinetics • metabolism • emphysema • retinoid
Inadequate dietary sources of retinoid precursors and/or increased expression of retinoid-metabolizing cytochrome P450 (CYP) enzymes likely contribute to retinoid deficiencies in target tissues. In vitro, several CYP families (CYP1A 2C, 2E1, 3A, and CYP26) are capable of catabolizing retinoic acid via 4-hydroxylation to 4-oxo-metabolites.9-11 All 3 isoforms of CYP26 (CYP26A1, CYP26B1, and CYP26C1) are induced by exposure to ATRA and result in efficient retinoid catabolism, with CYP26A and CYP26B1 selectively metabolizing ATRA and CYP26C1 metabolizing both ATRA and 9-cRA.12-16 Figure 1 outlines pathways involved in metabolism of the 3 major retinoic acid isomers: ATRA, 13-cRA, and 9-cRA.
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ATRA and 9-cRA are the most biologically active retinoic acid isomers, whereas 13-cis-retinoic acid (13-cRA) is considered less active and may require isomerization to ATRA in order to exert biologic function.17,18 Differences in ATRA and 13-cRA metabolism and pharmacokinetics have been reported in cancer patients.19-25 ATRA is rapidly cleared from plasma (plasma half-life <1 hour) and induces its own metabolism, and the 4-oxo-ATRA metabolite is rarely detected. In contrast, 13-cRA is slowly cleared from plasma (plasma half-life >13 hours) and does not induce its own metabolism, and repetitive dosing results in the accumulation of the 4-oxo-13-cRA metabolite to levels that exceed the parent drug.26
There are no detailed pharmacokinetic studies of ATRA and 13-cRA in patients with emphysema nor on their relative effects on serum levels of ATRA following repetitive dosing. It is possible, although not previously investigated, that retinoid metabolism or pharmacokinetics can be altered in patients with emphysema due to persistent effects from their cigarette smoking, relative pulmonary and systemic hypoxemia, or impaired hepatic drug extraction and/or metabolism secondary to compromised cardiac output. The Feasibility of Retinoids for the Treatment of Emphysema (FORTE) study provided a unique opportunity to perform a comprehensive pharmacokinetics analysis of acute and chronic administration of ATRA and 13-cRA in this population, to determine if a drug holiday every week allowed for sustained ATRA levels by preventing the autoinduction of drug metabolism, whether increasing the ATRA dose was sufficient to compensate for self-induced ATRA metabolism, and to determine if the isomerization of 13-cRA to ATRA could produce sufficient ATRA exposure. The FORTE study also provided the opportunity to relate drug and metabolite exposure to clinical and physiologic outcomes. The primary clinical results of the FORTE study were recently published.27
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Drug Administration Schedule
The 2 commercially available oral retinoids, ATRA (Vesanoid) and 13-cRA (Accutane), as well as a matching placebo, were supplied as 10-mg soft-gel caplets by Hoffmann–La Roche Laboratories (Nutley, New Jersey). Patients were randomized in a double-blind manner to 1 of 3 treatment arms—high-dose ATRA (HD-ATRA; 2 mg/kg/day), low-dose ATRA (LD-ATRA; 1 mg/kg/day), or 13-cRA (1 mg/kg/day)—and then randomized within each group at a 3:1 ratio to receive either active drug or a matching number of placebo caplets for 6 months. The drugs were administered in a divided dose twice daily. To minimize self-induced metabolism, ATRA was administered for 4 consecutive days with a 3-day drug holiday each week, whereas 13-cRA was given daily.27
Pharmacokinetic Study Design, Blood Sampling, Sample Handling, and Storage
FORTE was a 5-center study with comprehensive plasma retinoid pharmacokinetic samples collected at 1 center (University of Pittsburgh, n = 22 patients) and limited sampling (pretreatment and 3 hours posttreatment) collected at all centers. Plasma samples were collected on the first day (day 1) of treatment in all subjects and once again at either an early time point (2-4 weeks in half of subjects) or a later time point (12-16 weeks in the other half of subjects) to determine the long-term effects of intermittent ATRA and continuous 13-cRA dosing on retinoid levels and metabolism. Comprehensive day 1 and follow-up pharmacokinetic blood samples were obtained prior to and 1, 2, 3, 4, 6, 8, and 12 hours after retinoid administration. Limited pharmacokinetic (day 1 and follow-up) blood samples were obtained prior to and 3 hours after retinoid administration. Patients were instructed not to take the drug 12 hours prior to the follow-up pharmacokinetic studies and blood collected before and after dosing with study drug in the clinic. Plasma samples were separated from 7 mL of heparinized blood by a 10-minute centrifugation at 2000 g at 4°C. Because retinoids degrade when exposed to sunlight, plasma samples were collected into foil-covered tubes, processed in a dimmed room, and transported and stored at –70°C in amber-colored tubes until high-performance liquid chromatography (HPLC) analysis.
Bioanalytical Methods
Standards for ATRA, 13-cRA, 4-oxo ATRA, 4-oxo-13-cis-RA, and acitretin (the internal standard) were all kindly provided by Hoffmann–La Roche (Nutley, New Jersey). All-trans-retinol (retinol) was purchased from Sigma Chemicals. Plasma ATRA, 13-cRA, 4-oxo ATRA, 4-oxo-13-cis-RA, and retinol were extracted and measured using a modified HPLC method.28 Briefly, extractions and HPLC analyses were performed under yellow light. 13-cRA, 4-oxo-13-cRA, and 4-oxo-ATRA were separated by reverse-phase HPLC on a 250 x 4.6-cm Zorbax ODS column; ATRA and retinol were separated on a 250 x 4.6-mm Phenomenex C18 column. ATRA, 13-cRA, and their 4-oxo-metabolites were measured at 365 nm and retinol at 325 nm. Standard curves for retinol, ATRA, 13-cRA, and their 4-oxo-metabolites were established using artificial plasma consisting of 5% bovine serum albumin in 0.9% saline.21 All retinoid standard curves were linear (r2 > 0.97) over the 5- to 2000-ng/mL concentration ranges. The HPLC intra-assay and interassay coefficient of variation over this concentration range was <10%; the lower limit of detection of retinol, ATRA, 13-cRA, and the 4-oxo-metabolites was between 1 and 2 ng/mL. Plasma retinoid levels of 5 ng/mL were considered the lower limit of quantitation (LLOQ). The inaccuracy of the assay was 10% for plasma retinoid levels <100 ng/mL and less than 5% for plasma retinoid levels >100 ng/mL.
Pharmacokinetic Methods
Pharmacokinetic parameters were analyzed for all subjects who were enrolled into 1 of the 4 treatment groups and provided a complete set (both baseline and follow-up) of pharmacokinetic samples. Mean ± SEM plasma retinoid concentration-time profiles were plotted for each treatment group. Plasma retinoid concentration-time data were used in a noncompartmental analysis of the data (WinNonlin Version 5.2, Pharsight Corp, Mountain View, California). All pharmacokinetic parameters were summarized using mean and SEM. The pharmacokinetic parameters were estimated using the value of the lower level of quantification divided by 2 (LLOQ/2) for retinoid levels below detection. The plasma pharmacokinetic parameters estimated were peak levels (Cmax), time to Cmax (tmax), area under the concentration-time curve from time 0 to 12 hours (AUC0-12 h), terminal elimination half-life (t1/2), and apparent clearance (CL/F = Dose/AUC
). Only AUC values with the correlation coefficient (r2) in the regression analysis for terminal phase elimination rate constant >0.80 and the extrapolated AUC <20% of the AUC0-12 h value were used to calculate the t1/2 and CL/F parameters.
Statistical Methods
Comparisons between the day 1 and follow-up pharmacokinetic parameters for each treatment were made using the Wilcoxon matched pairs signed rank test. The mean and standard error of the mean for continuous variables and the number and percentage within each category for categorical variables were calculated. The analysis procedure used was a linear mixed-effect model, where response = treatment + period (day 1 and follow-up) + subject, with treatment and period as fixed effects and the subject as a random effect. The primary analysis was performed using untransformed values or the natural logarithms of ATRA AUC0-12 h, Cmax, and 3-hour plasma retinoid levels of the placebo and the 3 test treatments (LD-ATRA, HD-ATRA, and 13-cRA). Two pharmacodynamic responses, change in plasma ATRA levels (follow-up – day 1) and change in DLco (percentage predicted) (DLco at baseline – DLco at 6 months) for individual subjects in each treatment group were evaluated by linear mixed-effect modeling using day 1 and follow-up 3-hour plasma ATRA levels. Statistical significance for all testing was set at P > .05. The corresponding placebo groups for both ATRA doses and 13-cRA were pooled in the analysis presented here.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Comprehensive Retinoid Pharmacokinetics
Comprehensive plasma retinoid pharmacokinetics was obtained in 22 emphysema subjects on day 1, following the first administration of drug, and again at either 2 to 4 weeks or 12 to 16 weeks after starting therapy. Figure 2 shows the mean (±SEM) concentration-time profiles for ATRA, 13-cRA, and their 4-oxo metabolites for patients receiving 1 of the 3 active drug treatments (LD-ATRA, HD-ATRA, or 13-cRA). Corresponding pharmacokinetic parameters are summarized in Table II (ATRA groups) and Table III (13-cRA group). The median time to Cmax for plasma ATRA was 3 hours after ATRA dosing, and levels returned to the lower limit of quantitation by 12 hours in most subjects (Figure 2A,B). Auto-induction of ATRA-metabolizing CYP enzymes is known to limit chronic drug exposure, and the FORTE study addressed this issue by including a high-dose treatment group and by administering drug for only 4 days each week (providing a 3-day drug holiday). The administration of high-dose ATRA was effective in that both baseline and follow-up ATRA Cmax and AUC levels were significantly higher in the HD-ATRA group (P < .05). However, even though dose-dependent differences in ATRA Cmax and AUC persisted at follow-up, the follow-up values in both ATRA treatment groups were significantly lower (P < .05) than those measured on day 1 (Table II). The reduction in AUC at follow-up averaged 52.8% in the LD-ATRA group and 69.0% in the HD-ATRA group and was not associated with an increase in isomerization to 13-cRA, consistent with the induction of metabolizing enzymes despite the inclusion of a drug holiday. Furthermore, the decrease in follow-up ATRA levels was not associated with a significant increase in the 4-oxo-ATRA metabolite.
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13-cRA may induce independent effects on lung tissue repair and isomerizes to ATRA in plasma and tissues, thus providing an alternate strategy for the delivery of therapeutic retinoid levels. Plasma retinoid concentration-time profiles after 13-cRA treatment showed a time-dependent progressive increase in plasma 13-cRA and 4-oxo-13-cRA levels on day 1 and the attainment of steady-state plasma levels for both of these at follow-up, with the level of 4-oxo-13-cRA exceeding that of 13-cRA at follow-up (Figure 2C). Likewise, there was a time-dependent isomerization to ATRA and 4-oxo-ATRA following the first dose of drug and the attainment of steady-state levels of ATRA and 4-oxo-ATRA at follow-up. Analysis of the relationship between plasma ATRA and 13-cRA levels in 13-cRA-treated subjects showed a 10% maximum isomerization of 13-cRA to ATRA. In contrast to the reduction in ATRA plasma levels following chronic administration of ATRA, the daily administration of 13-cRA resulted in steady-state plasma ATRA levels at follow-up that equaled or exceeded the LD-ATRA Cmax on day 1.
Limited Plasma Retinoid Concentrations Obtained on All Subjects 3 Hours Postdosing
In addition to the comprehensive pharmacokinetics performed on a subset of patients, plasma retinoid levels were determined on all subjects 3 hours after the first dose of drug on day 1 and again at either their early or late follow-up visit. Three-hour plasma retinoid profiles by treatment group were similar to those seen in the comprehensive pharmacokinetic study. Dot plots, stratified by treatment group (LD-ATRA, HD-ATRA, and 13-cRA) and by study visit (day 1 vs follow-up), show the individual plasma ATRA concentrations for study participants (Figure 3). Administration of ATRA was associated with widely variable plasma ATRA levels, but on average, those treated with high-dose ATRA achieved the highest ATRA levels at both time points (P < .05). Mean plasma ATRA levels fell at the follow-up visit regardless of the dose of drug that patients were treated with. However, follow-up levels fell below 100 ng/mL in all subjects who were on low-dose ATRA, whereas 45% of subjects on HD-ATRA maintained levels >100 ng/mL (P < .05, Fisher exact test), consistent with the greater drug exposure documented by the comprehensive pharmacokinetic studies. The response pattern to 13-cRA was fundamentally different. On day 1, 3-hour plasma ATRA levels were uniformly low but were maintained or increased at the follow-up visit and reached levels that were equal to or exceeded that achieved by the low-dose ATRA group at the follow-up visits.
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Plasma Retinoid Pharmacokinetic/Pharmacodynamic Relationships
The relationships between pharmacokinetic parameters and study outcomes, including auto-induction of ATRA metabolism, drug toxicity, and effect on pulmonary function, were investigated using the plasma blood levels determined 3 hours after dosing on day 1 and at follow-up for the 116 emphysema patients who had complete data sets.
With respect to the auto-induction of metabolizing enzymes, there was a semilogarithmic relationship between day 1 plasma ATRA concentration and the change in plasma ATRA levels at follow-up for subjects treated with 1 of the active drugs (Figure 4A; r2 = 0.81; P = .0001). A specificity-sensitivity analysis (receiver operator curve) identified a day 1 plasma ATRA level of approximately 100 ng/mL as the cut point that best separated (96% specificity; 71% sensitivity) individuals with significantly lower plasma ATRA levels at follow-up from those with stable (<20% change from baseline) or increasing plasma ATRA levels (Figure 4B). This threshold effect may explain why individuals treated with 13-cRA, which produces only low ATRA plasma levels, experience stable or increasing ATRA levels at follow-up as compared to those treated with either high-dose or low-dose ATRA. There was no difference in the pattern of change over time in subjects who had follow-up levels at 2 to 4 weeks and those with plasma levels drawn at 12 to 16 weeks, suggesting that complete induction of ATRA metabolism occurs early after initiating drug therapy and allowing results from these 2 follow-up time points to be pooled (Figure 4C).
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Day 1 and follow-up ATRA levels were also examined for relationships to the primary lung function, quality of life, and CT scan changes that were observed in the FORTE study. A plot of the change in DLco (percentage predicted) from baseline to 6 months versus individual plasma ATRA levels measured on day 1 demonstrated a significant and inverse relationship (Figure 5). No relationship between the 6-month change in DLco (percentage predicted) and the plasma levels of ATRA and 13-cRA measured at the follow-up visits was observed (data not shown). As already published, there was also a relationship between the ATRA levels measured on day 1 and the change in CT scan emphysema score, but this effect was restricted to the high-dose ATRA group that achieved the highest day 1 plasma ATRA concentrations.27
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Our results demonstrate 2 major differences in retinoid metabolism and pharmacokinetics when ATRA and 13-cRA were administered orally to this study population. First, oral administration of ATRA (low and high dose) was characterized by a rapid (within 2 weeks) increase in ATRA clearance, consistent with the induction of metabolizing CYP450 enzymes, whereas the clearance of 13-cRA was slow and stable, allowing plasma 13-cRA levels to reach a steady state with continued daily dosing. Second, although no consistent changes in plasma 4-oxo-ATRA, 13-cRA, and 4-oxo-13-cRA levels were observed after ATRA administration, significant and time-dependent increases in ATRA, 4-oxo-ATRA, and 4-oxo-13-cRA levels that reached a steady state were the hallmarks of plasma retinoid pharmacokinetics after 13-cRA treatment. It has been reported that exposure to tobacco smoke can induce CYP450 enzymes and alter retinoid metabolism.11 However, all of our subjects were ex-smokers, and their pharmacokinetic profiles were similar to those published from studies in cancer patients.19-25 Differences in the pharmacokinetic profiles between ATRA and 13-cRA have been attributed to the specific and highly efficient catabolism of both ATRA and 4-oxo-ATRA by CYP26 isoforms. The high plasma 13-cRA and 4-oxo-13-cRA seen after 13-cRA treatment could reflect their slow metabolic clearance by non-CYP26 retinoic acid metabolizing cytochrome P450 enzymes, thus allowing ample time for isomerization to ATRA and 4-oxo-ATRA (Figure 1).
ATRA is one of the most biologically active retinoic acid isomers with a variety of in vitro assays, suggesting that it produces concentration-dependent effects on cell function at concentrations ranging from 0.1 to 5.0 µM (30-1500 ng/mL).29,30 In humans, ATRA Cmax levels in the range observed in this study have been associated with clinical responses, including complete remissions in children and adult patients with acute promyelocytic leukemia.19,23,31 In assessing the success of our different drug administration strategies, we therefore looked for the regimen that produced the highest plasma ATRA Cmax (or 3-hour postadministration levels) and AUC0-12 h on both day 1 and at follow-up. The best ATRA levels, within biologically effective ranges, were achieved and sustained in subjects treated with high-dose ATRA. Although high ATRA Cmax (>100 ng/mL) was obtained initially in 48% of subjects treated with low-dose ATRA, this was never maintained at follow-up. Furthermore, even though the plasma ATRA Cmax and AUC0-12 h values in those treated with 13-cRA exceeded those in the low-dose ATRA group at follow-up, subjects in the 13-cRA group never achieved sufficiently high ATRA exposure levels (Figure 3).
Another objective of this study was to evaluate 3 strategies to overcome self-induced ATRA metabolism and thus improve therapeutic efficacy. The first strategy was to administer ATRA on an intermittent schedule, an approach that had been previously shown to minimize self-induced ATRA metabolism in cancer patients.32 Unfortunately, we still observed significant decreases in plasma ATRA Cmax, 3-hour posttreatment levels, and AUC0-12 h when follow-up values were compared to those measured on day 1. We conclude that intermittent administration of ATRA for 4 consecutive days followed by a 3-day drug holiday each week was inadequate in overcoming self-induced ATRA metabolism. The second strategy was to increase the ATRA dose to approximately twice that recommended for treating promyelocytic leukemia (termed high dose in this study) as a mechanism to compensate for self-induced ATRA metabolism. Despite the failure of the intermittent strategy, the percentage of emphysema patients attaining plasma ATRA levels considered to be in the biologically active range at follow-up was significantly greater in those treated with high-dose ATRA than those treated with low-dose ATRA (42% vs 0%, respectively). We conclude that increasing the ATRA dose can partially compensate for changes in ATRA metabolism. The third strategy was to determine if the intrinsic isomerization of 13-cRA to ATRA would produce sufficient ATRA exposure. Our results show that plasma ATRA levels generated from the isomerization of 13-cRA were below the levels that would be expected to elicit biological effects. Based on these results, the most promising strategy to overcome self-induced ATRA metabolism is the administration of higher doses of ATRA. It is possible that a better designed and/or optimized intermittent administration schedule might still yield improvements in long-term drug levels, but at the risk of reducing the drug exposure to only a few days per week. Other approaches to overcome self-induced ATRA metabolism that were not evaluated in our study include the administration of ATRA in combination with inhibitors of cytochrome P450 enzymes33,34 and the development of new and biologically more active retinoic acid analogs that do not induce their own metabolism.35
Although the problem of self-induced ATRA metabolism has been previously studied, the FORTE study provided new insight by identifying a strong and negative relationship between initial 3-hour plasma ATRA levels and those at follow-up (Figure 4; r2 = 0.81; P = .0001). Furthermore, there appeared to be a threshold, 100 ng/mL, above which a significant reduction in follow-up ATRA levels could be predicted and below which the ATRA levels were likely to be maintained regardless of treatment group. Our pharmacodynamic findings suggest that the 100-ng/mL threshold may also be biologically important because treatment-related changes in DLco (percentage predicted) after 6 months of treatment (Figure 5), as well as subsequent improvements in quality of life and CT findings of emphysema 3 months later (previously reported),27 were all exposure related and predominantly occurring in subjects treated with high-dose ATRA. However, there was significant heterogeneity in the initial 3-hour plasma ATRA levels that might be related to other factors. As such, the failure to achieve levels above 100 ng/mL or to manifest biologic responses might relate to impaired gastrointestinal absorption, preexisting induction of the CYP450 enzymes involved in ATRA metabolism, or other factors that have not yet been identified.
In summary, our findings demonstrate that treatment with high-dose ATRA produces a superior pharmacokinetic profile when compared to treatment with either low-dose ATRA or 13-cRA, that intermittent dosing with ATRA for 4 days each week was ineffective in overcoming self-induced ATRA metabolism, and that administration of 13-cRA produces the most predictable and steady-state ATRA exposure but never results in high enough levels to produce biological effects. Although retinoid therapy offers a promising new approach to the treatment of emphysematous lung damage, the linkage between initial peak plasma ATRA levels and the induction of its own metabolism remains problematic.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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