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PHARMACOKINETICS AND PHARMACODYNAMICS |
From the Department of Clinical and Bioequivalence Research, Cipla Ltd, Mumbai, India.
Address for reprints: Shrinivas Purandare, PhD, Cipla Ltd, Mumbai Central 400008, Mumbai, India.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Pharmacokinetics • bioequivalence • lamivudine • stavudine • nevirapine
Lamivudine (3TC) and stavudine (d4T) are synthetic nucleoside analogs that are being increasingly used in comprising the core of an antiretroviral regimen for the treatment of HIV infection.9,10 In vivo, nucleoside analogs are phosphorylated intracellularly by endogenous kinases to putatively active 5'-triphosphate (3TC-TP and d4T-TP) derivatives that prevent HIV replication by competitively inhibiting viral reverse transcriptase and terminating proviral DNA chain extension.11-13 Nevirapine (NVP), a frequently used NNRTI, has been shown to induce superior virological suppression, improve immune function (increased CD4+ cell counts), and prevent clinical progression of multisymptomatic disease.14 Unlike NRTIs, NNRTIs do not require sequential intracellular phosphorylation to exert their antiretroviral effect. Highly lipophilic and essentially un-ionized at physiological pH, NVP disrupts the catalytic site of the enzyme reverse transcriptase, thereby inhibiting RNA- and DNA-dependent DNA polymerase activities.15
Single- and multiple-dose pharmacokinetic (PK) studies in nonhuman primates, healthy volunteers, and patients with HIV infections have demonstrated that mean absolute bioavailability of 3TC, d4T, and NVP after oral administration ranges between 84% and 99%. Following oral administration, the antiretrovirals are rapidly absorbed and extensively distributed. Secondary PK parameter plasma elimination half-lives (t1/2ß) are reported to be within 6 to 9 hours for 3TC, 1.2 to 2 hours for d4T, and 24 to 76 hours for NVP.16-19 The apparent oral plasma clearance (CL/F) for 3TC, d4T, and NVP ranges from 25 to 28 L/h, 22 to 26 L/h, and 1.5 to 2.5 L/h, respectively. In addition, apparent oral volume of distribution (Vd/F) is 150 to 233 L, 52 to 67 L, and 83 to 96 L for 3TC, d4T, and NVP, respectively.19-21
With the growing epidemic of acquired immunodeficiency syndrome (AIDS) in subcontinent and sub-Saharan African countries, particularly India and South Africa, it is essential that low-cost, disease-combative drug formulations are made available. HIV-infected patients in resource-poor countries are increasingly using relatively cheaper, generic, fixed-dose combinations that are preapproved by the World Health Organization (WHO). The generic-formulation fixed-dose combination of 3TC, d4T, and NVP is widely used in African countries.7 However, the PK of each component after the administration of the combination formulation has not yet been investigated. Hence, the objective of this study was to assess bioequivalence (BE) between the generic formulation with respect to the simultaneous administration of "proprietary-name formulations" of 3TC, d4T, and NVP. This single-center, open-label, randomized, crossover, 2-treatment study was conducted in 24 Indian, adult healthy volunteers under fasting conditions with at least 19 days of a drug-free washout period between the 2 treatments.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Study Design, Sample Collection, and Handling
The study was single center, randomized, and crossover in nature. The subjects were confined to the clinical study unit at least 16 hours prior to drug administration and until 24-hour postdose blood sample collection. The rest of the blood samples were collected as ambulatory samples. Food and water intake was controlled during the first 24 hours of the study. A computer-generated randomization code was used to ensure balanced permutation of the treatments. The subjects were randomly assigned to receive each of the following 2 treatment regimens:
Subjects received each treatment once in a crossover manner separated by at least 19 days of a drug-free washout period. A predose (0 hours, blank control) blood sample of 8 mL was collected from each volunteer in prelabeled glass tubes containing EDTA. On the study day at 7 AM, each volunteer ingested 1 tablet of either treatment A or 3 tablets of treatment B with 240 mL of water. Mouth and tongue checks were performed to ensure the subject had ingested all of the medication. Blood samples were then collected at 0.25, 0.5, 0.75, 1.0, 1.25, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 8.0, 12.0, 24.0, 48.0, 72.0, 120.0, 168.0, 216.0, 264.0, and 288.0 hours postdose. Within 30 minutes of blood collection, samples were centrifuged at 4°C at 3000 rpm for 10 minutes. Harvested plasma for each time point was aliquotted into 2 adequately labeled tubes. The samples were stored at –20°C until analysis.
Analysis of Plasma Sample
Plasma concentrations of 3TC, d4T, and NVP were simultaneously determined using a validated high-performance liquid chromatographic (HPLC) separation with tandem mass spectrometric (MS/MS) detection. The cartridges were initially preconditioned by sequential treatment with methanol and 50 mM phosphate buffer (pH 2.5) on a solid-phase extraction (SPE) vacuum manifold under low vacuum. Then, 0.5 mL of the thawed plasma sample was spiked with 50 µLofinternal standard (IS) acetaminophen (15 µg/mL) and 0.5 mL of 50 mM phosphate buffer (pH 2.5). The plasma samples were then loaded on the conditioned C18 cartridges, followed by washing with water and subsequent drying under full vacuum for 2 minutes. The cartridges were again washed with 0.5 mL hexane under low vacuum followed by 0.5 mL hexane under full vacuum for 2 minutes. The antiretrovirals were eluted using the elution mixture. The elution mixture consisted of methanol and dichloromethane (80:20, % v/v). The eluate was evaporated under nitrogen gas and reconstituted with 400 µL of reconstitution solution. The reconstitution solution consisted of methanol and water (90:10, % v/v). Then, 20 µL of the sample was injected onto the HPLC column. Chromatography was performed on a C18, 5-µm, 40 x 4.6-mm Kromasil column (Flexit, Pune, India), with the mobile phase consisting of methanol/2 mM ammonium acetate buffer (pH 4.5) (85:15, % v/v) at a flow rate of 0.5 mL/min. Unless otherwise noted, all reagents were of HPLC grade (Sigma, St.Louis, Mo).
Using the mass spectrometer (PE SCIEX API 2000, Foster City, Calif), antiretroviral drugs and IS were monitored in the positive ion mode using the multiple-reaction monitoring (MRM) transitions. The mass transitions of 230.2 amu to the product ion 111.9 amu, 225.2 amu to 126.9 amu, 267.3 amu to 226.0 amu, and 152.2 amu to 109.9 amu were monitored with dwell times of 50, 500, 100, and 400 msec for 3TC, d4T, NVP, and IS, respectively. The retention time was around 1 minute. The MacQuan software (Version 1.6, PE SCIEX) was used for the evaluation of chromatograms. Calibration and quality control standards were prepared in normal human plasma. Calibration standards demonstrated acceptable linearity (r 2 > 0.996) over a concentration range of 50 to 3000 ng/mL, 51 to 3000 ng/mL, and 47 to 4000 ng/mL for 3TC, d4T, and NVP, respectively. Quality control standards, ranging from 150 to 3590 ng/mL, determined that mean interassay accuracy and precision (percent coefficient of variation [%CV]) ranged from 93% to 106% and 2% to 5.4%, 96.1% to 103.2% and 2.3% to 8.4%, and 94.4% to 105.3% and 2.6% to 9.7% for 3TC, d4T, and NVP, respectively. The lower limit of quantification (LOQ) for the validated assay was 50, 51, and 47 ng/mL for 3TC, d4T, and NVP, respectively. Absolute percent recoveries of the antiretroviral from the plasma were 65%, 47%, 54%, and 49% for 3TC, d4T, NVP, and IS, respectively. The matrix effect, which may influence ionization of the analyte, was investigated by extracting "blank" plasma samples from at least 10 different sources. The final extract was reconstituted by injecting a solvent containing a known amount of analyte. The reconstituted extracts were analyzed and then compared to peak areas of the analytes. No matrix effect for the analytes was observed for 10 different plasma pools tested.
Pharmacokinetic Analysis
Noncompartmental PK analysis was employed to determine PK profiles of 3TC, d4T, and NVP for both kinds of treatment regimens and to analyze plasma drug concentration-time data. Concentrations below LOQ were assigned a zero value during estimation of PK parameters. The parameters Cmax and tmax were calculated directly from experimental observations of plasma concentrations. The AUC0
t, the area under the plasma concentration-time curve from 0 hours to the last measurable concentration (Clast), was calculated by a combination of linear and logarithmic trapezoidal methods. The AUC extrapolated to infinity (AUC
) was calculated by using the following equation: AUC = AUC0t + Clast/
z, where z is the terminal elimination rate constant. The z was estimated by performing log-linear regression on the concentration versus time data points that were determined to describe the terminal, linear elimination phase. Elimination half-life (t1/2ß) of the terminal log-linear phase was calculated by using the equation 0.693/z; CL/F was calculated as dose/AUC; and Vd/F was calculated by using the equation CL/z.
Statistical Analysis
Presuming 25% CV,20,22 a sample size of 24 subjects was considered to adequately power (>80%) the study to determine a 20% difference on a log scale in Cmax and AUC between treatments A and B. Primary PK parameters, Cmax and AUC, required in determining BE and statistical evaluation were performed by PK software WinNonlin Standard (Version 3.2, Pharsight, Mountain View, Calif) and by means of PROC GLM of SAS Release 8.2 (SAS Institute, Cary, NC). As per Committee for Proprietary Medicinal Products (CPMP) guidelines, the BE of 2 treatments would be concluded BE if 90% parametric confidence intervals (CIs) constructed for ratios (treatment A/treatment B) of the means of log-transformed PK parameters, AUC and AUC0t, were within the range of 80% to 125% and that for Cmax were within the range of 75% to 134%. The wider interval for Cmax was due to the inherent property of large intrasubject variability (>40%-50%) of 3TC.20 Pharmacokinetic parameters such as AUC, AUC0t, and Cmax (relative to treatment B) were evaluated using the 2 one-sided tests procedure for logarithmic transformed data. Wilcoxon's signed rank test was used to compare tmax. Comparisons of secondary PK parameters between Indians and other study populations were performed using the Student t test (Graphpad Prism v3.0, San Diego, Calif). Analysis of variance (ANOVA) was performed to assess period, treatment, and crossover effects.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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were comparable when administration was either as treatment A or B. The antiretrovirals were rapidly absorbed from either of the treatments, with median tmax for 3TC, d4T, and NVP being 1 hour, 0.5 hours, and 2.5 hours, respectively (Tables I, II, and III for 3TC, d4T, and NVP, respectively). Furthermore, the percentage of AUC extrapolated to infinity was similar for treatment A (5.8%, 11.28%, 5.85%) and treatment B (6.14%, 11.2%, 6.42%) for 3TC, d4T, and NVP, respectively. Moreover, the generic-formulation and single-simultaneous administered tablets exhibited no significant difference with respect to their secondary PK parameters (Table IV). Taken together, these results suggest that the PK profile of antiretrovirals was comparable in nature for either treatment. The secondary PK characteristics of d4T were consistent with literature reports.21,23 However, for 3TC, t1/2ß and Vd/F among Indian subjects were significantly (2- to 3-fold; P < .001) altered from the reported values for other study populations (Caucasians and Hispanics24,25; Table IV). For NVP, t1/2ß among Indian subjects was significantly higher than historical controls19 (Table IV).
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Assessment of Bioequivalence
To establish if the 2 treatments were BE, the PK parameter estimates were analyzed using natural log-transformed data. The geometric mean ratio (GMR; treatment A/treatment B) of Cmax, AUC0t, and AUC and their resultant 90% CI for 3TC, d4T, and NVP were within the range of 75% to 134% (Tables I, II, III). Untransformed results for the same parameters were consistent with the natural log-transformed data (data not shown). As 90% parametric CIs constructed for ratios were within the specified limits, the 2 treatments were considered BE in nature. ANOVA demonstrated significant formulation (treatment) (P < .05) and subject (sequence) effects (P < .005) for 3TC. Despite incorporating a sufficiently long washout period (>5 half-lives), a significant (P < .005) period effect for d4T was encountered. The intersubject %CV observed for all PK parameters, with the exception of tmax, was in the range of 19% to 35% (data not shown). Nonparametric statistical tests performed to calculate the 95% CI for tmax of the antiretroviral drug and 90% CI for the difference in tmax between treatments A and B revealed no statistically significant difference (Tables I, II, III).
Safety
Both the treatments were well tolerated, with little or no differences in the nature and frequency of adverse events. No serious clinical adverse events causing death, disability, hospitalization, or dropouts of the subjects were encountered. Reported mild adverse events, possibly related to treatments, were dizziness (8% for treatment A and 4% for treatment B), headache (4% for treatment A and 8% for treatment B), and skin rashes (4% for treatment A and 8% for treatment B). Poststudy clinical lab tests revealed normal results.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The PK profiles obtained for 3TC, d4T, and NVP in healthy subjects used in this study were consistent with the previously reported PK data in HIV-1-infected individuals.21,28,29 In both types of treatments, the Cmax of antiretrovirals was achieved within a few hours, suggesting rapid absorption and distribution. Moreover, the estimated value of AUC0t being more than 80% of the estimated value of AUC implied that the sampling scheme was sufficiently long to ensure an adequate description of the absorption phase. The results of the present study suggest that under fasting conditions, the generic formulation was BE to simultaneously co-administered proprietary-name formulation tablets. The GMR of Cmax, AUC0t, and AUC and the 90% CI were within 80% to 120% for untransformed data and within 80% and 125% for log-transformed data. In addition, a sample size of 24 subjects provided >90% power to detect a difference of at least 20% in AUC and Cmax between treatments A and B. A significant subject nested-within-sequence effect for 3TC suggests that between-subject variability (CV 
30%) significantly contributed toward total variability observed. This behavior is consistent with the characteristic of 3TC as a highly variable drug.20,24 A significant treatment effect for 3TC suggested that the study might have employed a sufficiently high number of volunteers. Although the exact cause of the period effect is not known, an insufficient washout period is unlikely to explain the period effect for d4T. However, as the effect is not coupled with sequence effect, the period effect appears to be insignificant in nature. With no serious clinical adverse events, it was concluded that both kinds of treatments were well tolerated.
It has been shown that a PK drug interaction did not exist between 3TC and NVP in HIV-1-infected individuals,29,30 and no statistically significant changes in d4T-PK were observed following the addition of NVP.31 Therefore, a PK drug interaction was unlikely to occur. Corroborating these observations, the present study suggests that primary PK characteristics of the antiretrovirals remain uninfluenced in the presence of each other. The lack of significant PK interactions between the antiretrovirals was predictable as the agents were excreted via different elimination pathways: 3TC is primarily eliminated via renal excretion, d4T undergoes metabolism via pyrimidine degradation and salvage mechanisms, and NVP undergoes oxidative metabolism followed by glucuronidation.22,28,32 This is an important finding in view of the fact that the activity profiles of the antiretrovirals are believed to be dependent on systemic exposure instead of the absorption rate. Nonsignificant differences among the AUC values observed between the 2 treatment regimens suggest that no changes in the dosing of antiretrovirals in the combination tablet are warranted with respect to their anti-virological activity.
The present study demonstrated that the estimate of t1/2ß of NVP in this study was significantly (P < .001) higher in comparison to the reported elimination half-life of 47 hours.19 However, apart from significant differences in study design, extent of sampling time points (32-96 hours19 vs 288 hours), and sampling times (4 datum points19 vs 25 datum points), there were significant differences in the sensitivities (25 ng/mL) of assay methodologies between the literature report and the present study (47 ng/mL). For 3TC, in comparison to historical data,25 Indian subjects used in this study exhibited a significantly lower elimination half-life. However, analogous to NVP, there were significant differences in study design and sampling times. Importantly, there were significant differences in the sensitivities of assay methodologies between the historical studies (5 ng/mL) and the present study (50 ng/mL). These differences may, in turn, significantly affect the estimation of t1/2ß and Vd/F. A shorter t1/2ß for 3TC has been previously reported in adult and pediatric patients.29,33 However, a major limitation of these studies was that the sampling period was until 12 hours, during which elimination was still taking place. The current study, despite being profiled until 288 hours, may suffer from a similar limitation as samples collected after 12 hours were below LOQ. These differences in the estimation of secondary PK characteristics of 3TC and NVP appear to be a reflection of differences in assay methodologies rather than study populations. Endorsing the observation, significant differences in secondary PK characteristics were not reflected in significant alterations in the extent of absorption.
It is noted that race, ethnicity, and disease state may have profound effects on the antiretroviral drug disposition of the generic formulation. Although there are insufficient data on the effects of gender, race, and concurrent underlying conditions on the PK of d4T, a recent study suggested that the PK profile of d4T in healthy South African volunteers34 was similar in nature to that presented in the present study. As antiretrovirals exhibit similar PK profiles in healthy subjects and in asymptomatic and symptomatic HIV-infected individuals, disposition of d4T is likely to be similar in nature in asymptomatic and symptomatic South African patients. In other studies, it was concluded that race and gender were not associated with the PK of 3TC35 and NVP,36 thus requiring no dose adaptations. Although the results presented here refer only to kinetics in healthy Indian subjects, it is likely that the drug disposition of the "generic formulation" in the symptomatic South African and Indian patient population would remain unaltered by race and disease state. A recent PK and pharmacodynamic study conducted in HIV-infected African patients in Cameroon demonstrated that antiretroviral drug concentrations achieved by the generic formulation were comparable with brand-name components of the regimen.37
Generic fixed-dose therapy offers various clinical advantages. As the extent of absorption (AUC) of single formulations of 3TC, d4T, and NVP appears to be similar under fasting and fed states,22,24,38 it is highly unlikely that PK characteristics of 3TC, d4T, and NVP generic-formulation tablets may be altered under the fed state. In addition, dose titration of 3TC/d4T/NVP need not be performed in patients with severe hepatic and renal impairment.20,23,39 HAART-containing NVP can be effectively used as a long-term PI-sparing regimen, thereby circumventing the metabolic side effects associated with PIs. In addition, the NVP-comprising generic formulation may be used to prevent maternal-fetal transmission during labor. Furthermore, a recent study demonstrated that a combination tablet of 3TC, d4T, and NVP significantly aided in the reduction of pill burden, which in turn is likely to enhance adherence to therapy, a critical component to ensure virological suppression.40 Availability of relatively cheaper yet effective generic antiretroviral formulations may aid in enhancing the quality of life of treatment-naive and treatment-experienced HIV patients.
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FOOTNOTES |
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Submitted for publication August 17, 2004; Revised version accepted November 22, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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