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Antimicrobial Agents and Chemotherapy, September 2008, p. 3035-3039, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00194-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Effects of Minocycline and Valproic Acid Coadministration on Atazanavir Plasma Concentrations in Human Immunodeficiency Virus-Infected Adults Receiving Atazanavir-Ritonavir

Robert DiCenzo,^1,2* Derick R. Peterson,² Kim Cruttenden,² Peter Mariuz,² Naser L. Rezk,³ Jill Hochreiter,¹ Harris Gelbard,² and Giovanni Schifitto²

University at Buffalo, Buffalo, New York,¹ University of Rochester, Rochester, New York,² University of North Carolina, Chapel Hill, North Carolina³

Received 11 February 2008/ Returned for modification 4 April 2008/ Accepted 11 June 2008

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Minocycline and valproic acid are potential adjuvant therapies for the treatment of human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine whether minocycline alone or in combination with valproic acid affected atazanavir plasma concentrations. Twelve adult HIV-infected subjects whose regimen included atazanavir (300 mg)-ritonavir (100 mg) daily for at least 4 weeks were enrolled. Each subject received atazanavir-ritonavir on day 1, atazanavir-ritonavir plus 100 mg minocycline twice daily on days 2 to 15, and atazanavir-ritonavir plus 100 mg minocycline twice daily and 250 mg valproic acid twice daily on days 16 to 30 with meals. The subjects had 11 plasma samples drawn over a dosing interval on days 1, 15, and 30. The coadministration of minocycline and valproic acid with atazanavir-ritonavir was well tolerated in all 12 subjects (six male; mean [± standard deviation] age was 43.1 [8.2] years). The geometric mean ratios (GMRs; 95% confidence interval [CI]) for the atazanavir area under the concentration-time curve from 0 to 24 h at steady state (AUC_0-24), the plasma concentration 24 h after the dose (C_min), and the maximum concentration during the dosing interval (C_max) with and without minocycline were 0.67 (0.50 to 0.90), 0.50 (0.28 to 0.89), and 0.75 (0.58 to 0.95), respectively. Similar decreases in atazanavir exposure were seen after the addition of valproic acid. The GMRs (95% CI) for atazanavir AUC_0-24, C_min, and C_max with and without minocycline plus valproic acid were 0.68 (0.43 to 1.06), 0.50 (0.24 to 1.06), and 0.66 (0.41 to 1.06), respectively. Coadministration of neither minocycline nor minocycline plus valproic acid appeared to influence the plasma concentrations of ritonavir (P > 0.2). Minocycline coadministration resulted in decreased atazanavir exposure, and there was no evidence that the addition of valproic acid mediated this effect.

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Cognitive impairment is a common complication of human immunodeficiency virus (HIV) infection, affecting one in five patients, and HIV infection is currently the most common cause of cognitive dysfunction in young people worldwide (2). Although the incidence of HIV-associated cognitive impairment has declined with the introduction of highly active antiretroviral therapy, the prevalence of this disorder will most likely increase due to the increased life span of HIV-infected individuals. Therefore, there is considerable interest in discovering adjuvant medications to treat HIV-associated cognitive impairment (6, 15).

Minocycline and valproic acid are both candidates for adjunctive therapy. Valproic acid may delay cognitive and behavioral changes associated with HIV infection through a number of mechanisms, including the modulation of glycogen synthase kinase 3-beta (8, 16). Minocycline is a tetracycline antimicrobial agent that has been shown in vitro and in animal models to mitigate a number of pathways that may lead to cognitive impairment, including microglia activation, glutamate toxicity, and caspase-independent and -dependent mitochondrion-mediated cell death (21). In addition, minocycline has been shown to delay the course of disease in mouse models of Huntington's disease and amyotrophic lateral sclerosis (19). Minocycline has also been shown to provide neuroprotection as well as reduce viral load in cerebral spinal fluid and brain homogenates in simian immunodeficiency virus-infected macaques that develop encephalitis, an animal model that recapitulates significant pathological features associated with HIV dementia (23). The above data have led to the implementation of a minocycline clinical trial in HIV-infected individuals with cognitive impairment (AIDS Clinical Trials Group protocol A5235).

In light of numerous reported protease inhibitor drug interactions and evidence supporting a correlation between protease inhibitor plasma concentrations and virologic response, it is important to consider the potential for protease inhibitor drug interactions before performing clinical trials (1, 4, 9, 10). This study was designed in response to interest in developing combination adjunctive therapy for the treatment of HIV-associated cognitive impairment. Having previously published results that failed to show a negative influence of valproic acid on lopinavir plasma concentrations, we decided to focus this study on the potential effects of minocycline with and without valproic acid (7). Since study of the entire class of protease inhibitors is cost prohibitive, we selected atazanavir based on its frequent use as a part of highly active antiretroviral therapy at our clinic. The purpose of this study was to determine whether minocycline alone or in combination with valproic acid would alter the atazanavir disposition when boosted by ritonavir in HIV-infected adults.

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Study subjects. Subjects were recruited from the North East AIDS Dementia cohort and the AIDS Clinical Trials Unit at the University of Rochester. HIV-infected subjects 18 years or older who met the criteria, including a stable antiretroviral regimen that included atazanavir and ritonavir for at least 4 weeks, were eligible for enrollment. Women who were pregnant or nursing and subjects taking a nonnucleoside reverse transcriptase inhibitor or any medication or herbal supplement known or suspected to interfere with the cytochrome P-450 (CYP450) isoenzyme system that was not cleared by the investigator were excluded.

Study design. The Research Subject Review Board at the University of Rochester approved this study, and all subjects were required to provide informed consent before any study procedures were initiated. All subjects received atazanavir (300 mg)-ritonavir (100 mg) once daily throughout the study, and all study drugs were given together with meals. Subjects received 100 mg minocycline twice daily on days 2 to 15 and 100 mg minocycline plus 250 mg valproic acid twice daily on days 16 to 30. Subjects arrived in the General Clinical Research Center (GCRC) in the morning on days 1, 15, and 30 after fasting since midnight the night before and received study drugs within 5 min of eating a standardized light breakfast. Each subject could choose from the following breakfast menu: toast (with or without jelly), bagel, an apple or apple sauce, banana, apple juice, and 1 cup of 1% milk. Dietary restrictions included no grapefruit-containing products within 3 days of the first visit and until discharge from the study and no citrus products on days 1, 2, 14, 15, 16, 30, and 31. Blood samples were drawn predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h after the morning dose of the study drug. Most subjects preferred staying overnight at the GCRC, while a few opted for discharge after the sample collection at 10 h and returned the next day for the 24-h-postdose sample collection. Minocycline and valproic acid were dispensed by the investigational pharmacy at the University of Rochester, and adherence was determined by subjects reporting the last three times of study drug administration before arrival at the GCRC.

Drug assays. Atazanavir and ritonavir plasma concentrations were measured using a New York State-certified method for plasma protease inhibitor quantitation utilized within the Pharmacotherapy Research Center Core Analytical Laboratory at the University at Buffalo (11). The lower limit of quantitation for atazanavir was 100 ng/ml. Samples with ritonavir concentrations that were below the lower limit of quantification (200 ng/ml) were measured using a previously published reverse-phase high-performance liquid chromatography assay at the University of North Carolina Center for AIDS Research, for which the lower limit of quantitation was 25 ng/ml (14).

Pharmacokinetic and statistical analyses. Standard noncompartmental techniques were used to calculate pharmacokinetic parameters using WinNonlin version 4.1 (Pharsight, Palo Alto, CA). The area under the concentration-time curve was determined using the linear trapezoidal rule for increasing values and the log trapezoidal rule for decreasing values, and the maximum observed concentration during the dosing interval was determined by visual inspection. If the sample drawn at the end of the dosing interval was not available or had a higher concentration than the sample collected at the previous time point, the concentration reported was determined by extrapolation using the estimated terminal elimination rate. The log transforms of pharmacokinetic parameters were compared between visits by using two-sided paired t tests at the 0.05 level of significance, corresponding with 95% confidence intervals (CI) for the geometric mean ratio (GMR).

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Minocycline and valproic acid coadministration was well tolerated in all 12 subjects who completed the study. Only two subjects experienced mild nausea which was self limiting. Data for gender, age, antiretroviral use, ethnicity, CD4 cell count, and viral load are given in Table 1. Subjects were allowed to receive nonantiretroviral medications at the discretion of the investigators as long as the medication was continued throughout the study. Concomitant nonantiretroviral therapy included three subjects receiving sulfamethoxazole-trimethoprim and two subjects receiving amitriptyline, gabapentin, or an albuterol inhaler. Nonantiretroviral therapy taken by at least one subject throughout the study included fenofibrate, rosiglitazone, enfuvirtide, pravastatin, atorvastatin, ranitidine, nicotine replacement, acyclovir, vancomycin for a Mediport implantable port infection, paroxetine, medroxyprogesterone, spironolactone, estradiol, trazodone, venlafaxine, dapsone, clonazepam, olanzapine, ferrous sulfate, escitalopram, loratadine, docusate, oxybutynin, erythropoietin, peginterferon alfa-2a, ribavirin, aspirin, alendronate, and testosterone.

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TABLE 1. Demographics and baseline clinical variablesa

Concomitant administration of minocycline decreased atazanavir plasma concentrations (Fig. 1 and Table 2). Minocycline coadministration resulted in a 33% decrease in the atazanavir area under the plasma concentration-time curve at steady state (AUC_0-24; P = 0.014), a 50% decrease in the plasma concentration 24 h after the dose (C_min; P = 0.022), and a 25% decrease in the maximum concentration during the dosing interval (C_max; P = 0.024). The GMRs (95% CI) for atazanavir AUC_0-24, C_min, and C_max with and without minocycline were 0.67 (0.50 to 0.90), 0.50 (0.28 to 0.89), and 0.75 (0.58 to 0.95), respectively. There was no evidence of a differential effect by baseline viral load status. The GMRs for AUC_0-24 were 0.66 and 0.68 for each subgroup of six patients with HIV-1 RNA levels below and above 50 copies/ml, respectively. Although this study was not designed to determine whether alterations in plasma concentration would result in an altered viral load, of the 11 subjects who had viral loads reported on both the screening and the final visit, only 1 subject had a slight increase in viral load (50 to 78 cells/ml) on the final visit, which was most likely a clinically insignificant blip.

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FIG. 1. Atazanavir plasma concentrations. Results shown are the means ± standard errors of atazanavir plasma concentrations for 12 subjects. Circles, squares, and diamonds represent atazanavir alone, atazanavir plus minocycline, and atazanavir plus minocycline and valproic acid, respectively.

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TABLE 2. Atazanavir and ritonavir pharmacokinetic resultsa

Similar decreases in atazanavir exposure were seen after the addition of valproic acid (Table 2). The GMRs (95% CI) for atazanavir AUC_0-24, C_min, and C_max with and without minocycline plus valproic acid were 0.68 (0.43 to 1.06; P = 0.080), 0.50 (0.24 to 1.06; P = 0.069), and 0.66 (0.41 to 1.06; P = 0.078), respectively. When the coadministration of minocycline is compared to the coadministration of minocycline plus valproic acid, the GMRs (95% CI) for atazanavir AUC_0-24, C_min, and C_max were 1.00 (0.57 to 1.77; P = 0.99), 1.01 (0.37 to 2.8; P = 0.99), and 0.89 (0.53 to 1.48; P = 0.63), respectively. The atazanavir half-life did not appear to be dependent on the drug regimen. The GMRs (95% CI) for atazanavir half-life with and without minocycline or minocycline plus valproic acid were 0.73 (0.52 to 1.02) and 0.85 (0.67 to 1.09), respectively.

We also analyzed the influence of minocycline and minocycline plus valproic acid coadministration on the plasma concentrations of ritonavir. Nine of the 12 subjects studied were included in the ritonavir pharmacokinetic analysis. One subject was receiving saquinavir, which interfered with the ritonavir assay, and two subjects had samples with plasma concentrations of ritonavir that were reported to be below the limit of detection. All of these subjects were observed to receive atazanavir and ritonavir during their visits, and atazanavir exposure was lower during minocycline coadministration in this subset of nine subjects (atazanavir AUC_0-24 GMR [95% CI] = 0.68 [0.52 to 0.88]). Coadministration of minocycline or minocycline plus valproic acid did not have a statistically significant influence on ritonavir plasma concentrations (Table 2 and Fig. 2; P was >0.2 for all comparisons). The GMRs (95% CI) for ritonavir AUC_0-24, C_min, and C_max with and without minocycline were 0.90 (0.50 to 1.60), 1.23 (0.59 to 2.53), and 0.95 (0.54 to 1.68), respectively, while the GMRs (95% CI) for ritonavir AUC_0-24, C_min, and C_max with and without minocycline plus valproic acid were 0.86 (0.39 to 1.90), 1.16 (0.38 to 3.60), and 0.87 (0.40 to 1.90), respectively.

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FIG. 2. Ritonavir plasma concentrations. Results shown are the means ± standard errors of ritonavir plasma concentrations for nine subjects. Circles, squares, and diamonds represent ritonavir alone, ritonavir plus minocycline, and ritonavir plus minocycline and valproic acid, respectively.

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We found that minocycline decreased atazanavir plasma concentrations in HIV-infected adults, and we did not see any evidence that valproic acid would influence this interaction. Most protease inhibitors, including atazanavir and ritonavir, are substrates for CYP450 enzymes and transporter proteins, such as P glycoprotein, making them particularly susceptible to drug interactions involving drug absorption, tissue distribution, metabolism, and elimination (13). Although there is some evidence that minocycline is at least partially metabolized by CYP450 enzymes, there is little evidence that minocycline influences the disposition of drugs by inducing this enzyme system (3, 17). There are case reports of minocycline interacting with theophylline, but minocycline increased theophylline exposure and theophylline is metabolized primarily by a CYP450 enzyme (CYP1A2) that is not thought to influence the disposition of atazanavir (12, 20). Like other tetracyclines, minocycline has the potential to decrease exposure to oral contraceptives; however, the interference of enterohepatic recirculation via the alteration of bacterial flora is the purported mechanism of this interaction (24). Although tetracyclines have been shown to increase the absorption of digoxin, a P-glycoprotein substrate, this interaction is thought to be due to decreased bacterial metabolism rather than to an influence on efflux pump activity (25).

Protease inhibitors are weak bases; therefore, elevations in gastric pH may lead to decreased drug solubility and absorption. Although there is evidence that metal cations chelate with tetracyclines to form unabsorbable complexes and that antacids may alter tetracycline absorption by increasing gastric pH, we were unable to find any evidence that minocycline binds to atazanavir or alters gastric pH (5, 22). Since the half-life was not significantly altered, decreased absorption may be the most likely explanation for the effect of minocycline on atazanavir plasma concentrations. However, our inability to detect an influence on the half-life was limited by the sampling strategy in which no samples were drawn between 10 and 24 h after the dose and by the small sample size. Since atazanavir absorption may be more sensitive than the absorption of other protease inhibitors to elevated gastric pH, more study is needed to determine whether minocycline will influence the absorption of other protease inhibitors.

Since ritonavir boosts atazanavir exposure, we also investigated the potential for minocycline to influence atazanavir indirectly by altering ritonavir plasma concentrations. Neither minocycline nor minocycline plus valproic acid coadministration resulted in a statistically significant change in any of the ritonavir pharmacokinetic parameters tested. However, comparisons between visits were limited by the inclusion of only 9 of the 12 subjects enrolled. Although we observed a net tendency for higher atazanavir and ritonavir concentrations during valproic acid coadministration (Fig. 1 and 2), neither the atazanavir nor the ritonavir AUC_0-24 appears to be influenced by valproic acid coadministration (Table 2). More study is necessary before concluding that minocycline coadministration does not influence ritonavir exposure.

There are a number of additional limitations to this study. Since we included HIV-infected adults and did not attempt to alter their medications, some subjects were receiving concomitant medication that may have influenced atazanavir plasma concentrations. However, the influence of concomitant medications was limited by instructing subjects to continue all concomitant medications throughout the study and using a paired design. Although one subject received saquinavir and a gastric acid buffering agent, ranitidine, a comparison of atazanavir results (atazanavir with and without minocycline) to those obtained with this subject excluded showed that inclusion of this subject did not appear to influence atazanavir AUC_0-24 (P = 0.014 versus P = 0.029), C_min (P = 0.022 versus P = 0.039), or C_max (P = 0.024 versus P = 0.05) results. Another limitation of this study is the inability to determine whether atazanavir-ritonavir influences valproic acid exposure. Ritonavir may induce the glucuronidation of valproic acid. Sheehan and colleagues reported a clinically significant case of decreased valproic acid concentration during lopinavir-ritonavir coadministration (18). Although we reported no evidence that lopinavir-ritonavir decreased valproic acid trough plasma concentrations during a previous study, both of our studies used a low dose of valproic acid (7). There is the potential that higher doses of valproic acid may influence the effect of minocycline on atazanavir and ritonavir or that clinically significant decreases in valproic acid exposure may be seen at higher doses. Lastly, the high degree of inter- and intrapatient variabilities in atazanavir and ritonavir exposures may have limited our ability to find a difference when regimens were compared.

In summary, minocycline coadministration resulted in decreased atazanavir exposure, and there was no evidence that the addition of valproic acid mediated this effect or that this effect was indirectly influenced through altered ritonavir exposure. Since the mechanism of this interaction is unknown, more studies are necessary to determine whether minocycline would alter the plasma concentrations of other protease inhibitors. Lastly, a longer period of observation is needed to determine whether the pharmacokinetic interaction observed in this study influences treatment response.

 
This work was supported by grant P01 MH64570; in part by a General Clinical Research Center Grant, 5M01-RR 00044, from the National Center for Research Resources, NIH, and the University of North Carolina at Chapel Hill Center for AIDS Research (CFAR); NIH-funded program grant P30 AI50410; and the University at Buffalo Pharmacotherapy Research Center Core Analytical Laboratory.

 
* Corresponding author. Mailing address: University of Rochester Medical Center, Infectious Disease Division, 601 Elmwood Avenue, Box 689, Room 3-6209, Rochester, NY 14642. Phone: (585) 275-6249. Fax: (585) 442-9328. E-mail: robert_dicenzo{at}urmc.rochester.edu

Published ahead of print on 23 June 2008.

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Antimicrobial Agents and Chemotherapy, September 2008, p. 3035-3039, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00194-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by DiCenzo, R. Articles by Schifitto, G. Search for Related Content PubMed PubMed Citation Articles by DiCenzo, R. Articles by Schifitto, G.