An Open-Label Evaluation of the Effect of Coadministering Desvenlafaxine 100 mg on the Pharmacokinetics of Aripiprazole in Healthy Subjects

Copyright: © 2013 Nichols AI, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. An Open-Label Evaluation of the Effect of Coadministering Desvenlafaxine 100 mg on the Pharmacokinetics of Aripiprazole in Healthy Subjects


Introduction
Major depressive disorder (MDD) has a lifetime prevalence in the United States of approximately 17% and is associated with significant disability [1]. High rates of incomplete response with first-line antidepressant therapy have been observed in a number of large scale studies [2,3]. Treatment options for patients with residual symptoms despite antidepressant treatment include dose optimization, combining two antidepressants, and augmentation with a psychotropic agent from another therapeutic class, such as lithium or an atypical antipsychotic [4]. Results of double-blind, placebo-controlled clinical trials of atypical antipsychotics used adjunctively with an antidepressant in patients with incomplete response to antidepressant treatment support the efficacy of this treatment option for further alleviating depressive symptoms and improving outcomes [4][5][6][7][8].
Aripiprazole is an atypical antipsychotic that is a partial D 2 dopamine and serotonin 1A agonist that is approved by the US Food and Drug Administration (FDA) as an adjunctive treatment for MDD [9,10]. Aripiprazole is primarily metabolized by dehydrogenation and hydroxylation through the cytochrome P450 (CYP) 3A4 and -2D6 enzymes, as well as N-dealkylation via CYP3A4 [10]. As a result of this metabolic profile, concomitant administration of aripiprazole with a drug that inhibits or induces CYP2D6 or -3A4 may affect the metabolism of aripiprazole [11]. For example, quinidine 166 mg/d, a significant CYP2D6 inhibitor, has been shown to increase the area under the plasma concentration curve (AUC) of aripiprazole by 112% and decreased the AUC of dehydro-aripiprazole by 35% when coadministered with a single dose of aripiprazole 10 mg [10]. The clinical effect of aripiprazole is thought to be primarily driven by the parent compound but is also partially dependent on the primary metabolite, dehydro-aripiprazole, so inhibition of CYP3A4 and/or -2D6 may impact the efficacy or tolerability of aripiprazole [10].
A number of antidepressants are known to inhibit the activity of CYP2D6 to varying degrees [12]. As a result, dose adjustments are recommended when aripiprazole and CYP2D6 inhibiting antidepressants are used concomitantly; however, no dose adjustments are recommended when using aripiprazole adjunctively in MDD patients [10]. Desvenlafaxine (administered as desvenlafaxine succinate) is a serotonin-norepinephrine reuptake inhibitor approved by the FDA for the treatment of MDD at a dose of 50 mg/d [13] and has demonstrated efficacy in a number of randomized, placebo-controlled clinical trials [14][15][16]. The metabolic profile of desvenlafaxine suggests that it has a low risk for CYP mediated drug-drug interactions because this agent does not substantially inhibit or induce the activity of these enzymes; instead, the metabolism of desvenlafaxine primarily occurs through phase II glucuronidation and to a lesser degree through CYP3A4 [13,17,18]. The objective of the current study was to assess the potential of desvenlafaxine to interfere with the pharmacokinetics of aripiprazole and dehydro-aripiprazole when administered concomitantly using a population of healthy, nondepressed subjects.

Study design
This open-label, single-center, 2-period, sequential, inpatient/ outpatient study was performed with a population of healthy subjects that did not meet criteria for MDD. A screening period occurred during the 28 days prior enrollment (Table 1). During period 1, subjects entered the inpatient setting for 3 days and 2 nights and received a single oral dose of aripiprazole 5 mg followed by blood sampling for pharmacokinetic analyses over the subsequent 14 days. During period 2, subjects reentered the inpatient setting for 9 days and 8 nights and received desvenlafaxine 100 mg once daily for 19 days until steady state concentrations were reached. On day 7 of period 2, subjects were coadministered a single dose of aripiprazole 5 mg followed by 14 days of blood sampling for pharmacokinetic analyses.

Inclusion criteria
Eligible study participants were required to be physically healthy, 18 to 55 years of age, and have body mass index (BMI) 17.5 to 30.5 kg/m 2 with a total body weight >50 kg. Physical health was defined as having no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead electrocardiogram and clinical laboratory tests. In addition, eligible subjects were required to be nonsmokers or smokers of <5 cigarettes daily and be able to abstain from tobacco use during the inpatient period.

Exclusion criteria
Subjects were ineligible to participate in this study if they had any evidence or history of clinically significant disease that would interfere with study completion or collection of accurate results in this study, including alcohol abuse or a positive urine drug screen. Pregnant or nursing females or females of childbearing potential who are unwilling or unable to use an acceptable method of nonhormonal contraception ≥ 14 days before the first dose of study medication were excluded. Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) before the first dose of study medication was prohibited. Eligible subjects could not have donated blood of approximately 1 pint (500 mL) within 56 days before dosing. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation, or use of an investigational product administration that may interfere with the interpretation of study results would make the subject ineligible for enrollment.

Pharmacokinetic analyses
Blood samples of 4 mL, to provide a minimum of 1.5 mL plasma for pharmacokinetic analysis, were collected at specified times and stored in appropriately labeled tubes containing K2-EDTA. Blood samples were placed in an ice-water bath immediately then centrifuged at 1700 g for 10 minutes at 4°C. Plasma samples were stored at -20°C within 1 hour of collection and analyzed for aripiprazole and dehydroaripiprazole concentrations by Cetero Research (Houston, TX) using a validated liquid chromatography/tandem mass spectrometry (LC/ MS/MS) method. Calibration responses were linear over the range of 0.100 to 80.0 ng/mL for both aripiprazole and dehydro-aripiprazole using a weighted linear least squares regression with a lower limit of quantification of 0.100 ng/mL. Desvenlafaxine concentrations were also assayed using a validated LC/MS/MS method; calibration responses were linear over the range of 2.0 to 500.0 ng/mL. The primary pharmacokinetic end point for this study was aripiprazole area under the plasma concentration curve (AUC) over infinite time (AUC inf ). Secondary end points included dehydroaripiprazole AUC inf , aripiprazole and dehydro-aripiprazole AUC to the last measurable concentration (AUC last ), peak plasma concentration (C max ), time to C max (t max ), terminal elimination half-life (t 1/2 ), apparent clearance (CL/F), and apparent volume of distribution (V Z /F).
Plasma analyte concentrations at time 0 (C 0 ) of period 2, immediately before administration of the second dose of aripiprazole, were evaluated for possible carry-over effect by numerically adjusting AUC inf and AUC last based on pharmacokinetic superposition methods [19], and comparing original and corrected AUC inf and AUC last values. The equations used to calculate corrected AUC inf (AUC infcorr ) and corrected AUC last (AUC lastcorr ) are: where, k el is the terminal phase rate constant for period 2, calculated by a linear regression of the log-linear concentration-time curve.

Safety analyses
An adverse event (AE) was defined as any untoward medical occurrence, defined using abnormal test findings, clinically significant symptoms and signs, changes in physical examination findings, hypersensitivity, or progression/worsening of underlying disease. Additionally, AEs may include the signs or symptoms resulting from drug overdose, drug withdrawal, drug interactions, extravasation, and exposure in utero. A serious AE (SAE) was an event that resulted in death, was life threatening, required inpatient hospitalization Inpatient confinement PK= Pharmacokinetics *Screening was conducted within 28 days before aripiprazole administration in study period 1 † Start of study period 2 was within 7 days of day 14 of study period or prolonged existing hospitalization and resulted in persistent or significant disability or congenital anomaly. Any AE occurring or increasing in severity after the first administration of study drug were counted as treatment emergent.

Statistical analysis
Plasma concentration data and pharmacokinetic end points of aripiprazole and dehydro-aripiprazole are summarized using descriptive statistics. The interactive effect on pharmacokinetic parameters was determined by calculating 90% confidence intervals (CIs) in relation to the estimated difference between groups using a mixed-effects model, based on natural-log-transformed data and implemented with an SAS Proc Mixed model, with the restricted maximum likelihood estimation method and Kenward-Roger degreesof-freedom algorithm. Natural-log-transformed aripiprazole AUC inf , AUC last , and C max and dehydro-aripiprazole AUC inf , AUC last , and C max were compared between monotherapy (ie, aripiprazole administered alone; reference treatment) and combination therapy (desvenlafaxine + aripiprazole; test treatment) using a mixed-effects model, with treatment as a fixed effect and subject as a repeated random effect. Adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (test/reference) and 90% CIs for the ratios.
Lack of an interaction was concluded if the 90% CIs for the ratio of adjusted geometric means for AUC last , AUC inf , and C max fell wholly within 80% to 125%. Pharmacokinetic data from subjects predicted to be CYP2D6 poor metabolizers based on CYP2D6 genotyping were excluded from statistical analyses.

Subject disposition
Of the 38 enrolled subjects, 36 completed the aripiprazole alone administration phase (period 1), 35 completed the desvenlafaxine alone administration phase (period 2; days 1-6), and 33 completed the desvenlafaxine and aripiprazole combination phase (period 2; days 7-19). All 38 subjects were analyzed for pharmacokinetic and safety outcomes. Five subjects discontinued the study: 2 were lost to followup; 1 was no longer willing to participate; and 2 violated the protocol. Of the 38 enrolled subjects, 20 were male, 32 were white, and 6 were black. The mean age of this population was 35.2 years (range: 23-46 years), while the mean weight was 74.3 kg and mean BMI was 26.4 kg/ m 2 .

Pharmacokinetic analyses
Aripiprazole plasma concentrations: Carry-over of aripiprazole concentrations from period 1 was observed with quantifiable plasma concentrations of aripiprazole at Time 0 prior to the second administration of aripiprazole in 24 of 35 subjects. Mean (SD) aripiprazole concentration immediately before the second dose of aripiprazole was 0.23 (0.25) ng/mL, approximately 1% of the C max values for either the first or second dose of aripiprazole. In addition, the difference between original and corrected AUC values was minimal, approximately 1.6% and 1.8% for AUC inf and AUC last , respectively. Therefore, the original and not corrected values for AUC and C max were used for statistical analysis.
Following single-dose administration of aripiprazole 5 mg alone and with steady-state desvenlafaxine 100 mg once daily, median plasma aripiprazole concentration-time profiles were nearly superimposable ( Figure 1). The geometric mean aripiprazole AUC inf was generally the same whether aripiprazole was administered alone (1494 ng•h/ mL), although a slight increase was observed with concomitantly administered desvenlafaxine (1604 ng•h/mL; Table 2). In addition, the geometric mean C max of aripiprazole was the same (24.7 ng/mL) whether aripiprazole was administered alone or with desvenlafaxine. Median t max was extended by 1 hour for aripiprazole alone (3.0 hours) in relation to when coadministered with desvenlafaxine (4.0 hours); however, the t 1/2 decreased with the coadministration of desvenlafaxine (84.2 hours) compared with aripiprazole alone (85.2 hours). Overall, statistical comparisons showed that coadministration of aripiprazole with steady-state desvenlafaxine did not significantly alter aripiprazole AUC last , AUC inf , and C max (Table 3), as reflected by the ratio of adjusted geometric means (90% CI) of approximately 106.4% (102.0%, 111.0%), 106.0% (101.4%, 110.8%), and 101.1% (92.9% to 109.9%), respectively. All of these values were within the acceptance range of 80% to 125%, demonstrating bioequivalence. In addition, the difference between original and corrected AUC values was minimal, on average approximately 1.3% and 9.3% for AUC inf and AUC last , respectively. Due to the small contribution of carryover for C max and AUC values, the uncorrected values were used for statistical analyses.
Similar to the observed plasma aripiprazole concentration-time profile, median plasma concentrations of dehydro-aripiprazole were equivalent whether aripiprazole was administered alone or with steady-state desvenlafaxine (Figure 2). The other pharmacokinetic parameters for dehydro-aripiprazole were also similar ( Table  2). Dehydro-aripiprazole geometric mean C max was comparable whether aripiprazole was administered alone (3.01 ng/mL) or with desvenlafaxine (3.20 ng/mL); however, median t max increased with the coadministration of desvenlafaxine (59.9 hours vs 71.9 hours). Results of statistical comparisons of pharmacokinetic parameters for dehydroaripiprazole are shown in Table 4. As AUC inf could only be calculated for 18 of 38 subjects in period 1 and 14 of 35 subjects in period 2, AUC last rather than AUC inf was determined to be a more appropriate measure of exposure. Geometric means for dehydro-aripiprazole AUC last was 599.6 ng•h/mL for aripiprazole alone and 630.9 ng•h/ mL when desvenlafaxine was coadministered. Coadministration of desvenlafaxine with aripiprazole did not significantly impact the geometric means of dehydro-aripiprazole AUC last and C max , as reflected by the ratio of adjusted geometric means (90% CI) of 105.2% (101.3%, 109.3%) and 106.3% (101.0%, 111.9%), respectively, which were within the bioequivalence range. Dehydro-aripiprazole AUC last for the 4 subjects with an IM genotype ranged from 381 to 500 ng•h/mL, which was lower than the average AUC last value. In contrast, the AUC last for dehydro-aripiprazole for the subject with the UM genotype was higher (725 ng•h/mL) than the average AUC last value.
Desvenlafaxine plasma concentrations: Predose plasma concentrations of desvenlafaxine were quantified for samples obtained prior to the second administration of aripiprazole. Quantifiable concentrations of desvenlafaxine were observed in all 35 subjects and ranged from 47.6 to 389 ng/mL.

Safety analyses
There were no deaths or other SAEs and no discontinuations, temporary discontinuations, or dose reductions due to an AE in this study ( Table 5). The majority of AEs throughout the study were considered treatment-related, but most were mild in severity; no severe AEs were reported. The most frequent AE was nausea, reported by 6 subjects who received aripiprazole alone, 2 subjects who received desvenlafaxine alone, and 5 subjects who received aripiprazole with desvenlafaxine. Hot flushes were reported by 7 subjects while receiving aripiprazole. Of the treatment-related AEs, nausea (n=1), vomiting (n=2), headache (n=1), and presyncope (n=1) were moderate in severity; all AEs occurred during administration of aripiprazole. All other AEs were mild in severity.

Discussion
The present study examined the effect of desvenlafaxine 100 mg on the pharmacokinetics of aripiprazole 5 mg when coadministered to a population of healthy subjects. The results demonstrate that steadystate desvenlafaxine at twice the recommended dose for treating MDD did not significantly alter the pharmacokinetics of either aripiprazole or its active metabolite dehydro-aripiprazole. In conjunction with previously conducted pharmacokinetic studies that coadministered desvenlafaxine with the CYP2D6 substrates desipramine and tamoxifen and the CYP3A4 substrate midazolam, the results of the current study demonstrate that desvenlafaxine does not significantly affect the activity of the CYP2D6 and -3A4 enzymes [20].
In contrast to the results observed here with desvenlafaxine, a previously conducted study demonstrated that the coadministration of aripiprazole with the potent CYP2D6 inhibiting antidepressants fluoxetine and paroxetine significantly increased the steady-state dose-adjusted serum concentrations of aripiprazole by approximately 45% (P<0.05) compared to aripiprazole alone [21]. In addition, when paroxetine was administered concomitantly with aripiprazole to genotyped CYP2D6 EMs, clearance of aripiprazole decreased by 58%, C max increased 39%, and AUC inf increased 140% compared to when aripiprazole was administered alone [22]. The effect of concomitant paroxetine was smaller in IM individuals (-23%, +27%, and +30%, respectively). A therapeutic drug monitoring analysis of aripiprazole suggests that concentrations of aripiprazole and dehydro-aripiprazole are associated with efficacy and tolerability, and individuals with particularly low or high levels of either or both compounds may be at risk for a lower therapeutic response or increased side effects, respectively [23]. A post hoc analysis conducted by Nelson et al. [24] (17) AUC inf = area under the plasma concentration curve over infinite time; C max = peak plasma concentration; N= number of subjects in the treatment group; n= number of subjects where AUC inf was determined for aripiprazole, and where t ½ and AUC inf were determined for dehydro-aripiprazole; t ½ = half-life; t max = time to peak plasma concentration * Geometric mean (geometric %CV) † Median (range) ‡ Arithmetic mean (%CV)     [25,26]. Different elimination pathways account for the majority of desvenlafaxine (renal elimination and glucuronidation [13]) and aripiprazole (CYP2D6 and CYP3A4 metabolism [10], clearance, and coadministration of desvenlafaxine does not significantly impact the pharmacokinetics of aripiprazole. Desvenlafaxine therefore may be a safer and better tolerated option than several other antidepressants that inhibit CYP2D6 for adjunctive therapy with aripiprazole to treat MDD in patients not adequately responding to treatment with an antidepressant. No new or unexpected safety concerns related to administration of desvenlafaxine 100 mg were observed in this study. Furthermore, the coadministration of desvenlafaxine with aripiprazole appeared to be safe and generally well tolerated. A study limitation was the use of a design that did not allow sufficient wash-out between doses of aripiprazole to exclude the presence of the drug and metabolite at the time of administration of the second dose. This shortcoming was primarily due to the limited information available in the literature for the t 1/2 for aripiprazole and dehydro-aripiprazole at the time the study design was developed [10,[27][28][29] and a desire to not unnecessarily prolong study duration. However, the terminal log-linear elimination for both aripiprazole ( Figure 1) and dehydro-aripiprazole ( Figure 2) was well established by 6 days following aripiprazole administration. The second dose of aripiprazole was administered after a 14-to 21-day washout plus the 7-day period during which steady-state desvenlafaxine concentrations were attained, giving a total of 21 to 28 days between aripiprazole doses. The impact of this carryover can be determined based on calculation of corrected values for AUC last and AUC inf . Based on the calculation of corrected values, the mean percentage increase in these AUC values was 1.6% to 1.8% for aripiprazole and 1.3% to 9.3% for dehydro-aripiprazole. As this carryover was minimal, it was determined that calculation of PK parameters for the second treatment period did not need to be modified before making statistical comparisons of aripiprazole and dehydro-aripiprazole PK with and without coadministration of desvenlafaxine. If carry-over were to affect the statistical comparison between aripiprazole and aripiprazole plus desvenlafaxine, it would be to increase concentrations of aripiprazole and metabolite following the second aripiprazole dose. Thus, a conservative approach in testing for bioequivalence between the 2 doses was followed. The statistical comparisons between pharmacokinetic profiles demonstrated bioequivalence for both aripiprazole and dehydro-aripiprazole without and with the presence of desvenlafaxine, even though no adjustments for the presence of minor concentrations of aripiprazole and dehydroaripiprazole were made.
Generalization of results to an MDD patient population that may be using multiple medications is limited by the use of healthy subjects in this study. In addition, because the study was primarily conducted to assess pharmacokinetic outcomes, the sample size was relatively small for fully assessing safety. Further analyses will need to assess the efficacy and safety of coadministering desvenlafaxine and aripiprazole in patients with MDD.

Conclusion
Using the assessed pharmacokinetic parameters of both aripiprazole and its metabolite dehydro-aripiprazole, bioequivalence criteria were met when aripiprazole 5 mg was administered alone and coadministered with steady-state desvenlafaxine 100 mg. Thus, it appears that desvenlafaxine (at twice the dose recommended for treatment of MDD) does not significantly alter the pharmacokinetics of aripiprazole, lending support for the safety of using these agents in combination.