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Kinetics and Dynamics of Intravenous Adinazolam, N-Desmethyl Adinazolam, and Alprazolam in Healthy Volunteers

From the Department of Pharmacology and Experimental Therapeutics, the Department of Neurology, and the Division of Clinical Pharmacology, Tufts University School of Medicine and Tufts-New England Medical Center, Boston.

Address for reprints: David J. Greenblatt, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The pharmacokinetics and pharmacodynamics of adinazolam mesylate (10 mg), N-desmethyl adinazolam mesylate (NDMAD, 10 mg), and alprazolam (1 mg) were investigated in 9 healthy male subjects in a randomized, blinded, single-dose, 4-way crossover study. All drugs were intravenously infused over 30 minutes. Plasma adinazolam, NDMAD, and alprazolam concentrations, electroencephalographic (EEG) activity in the ß (12-30 Hz) range, performance on the Digit Symbol Substitution Test (DSST), and subjective measures of mood and sedation were monitored for 12 to 24 hours. Mean pharmacokinetic parameters for adinazolam, NDMAD, and alprazolam, respectively, were as follows: volume of distribution (L), 106, 100, and 77; elimination half-life (hours), 2.9, 2.8, and 14.6; and clearance (mL/min), 444, 321, and 84. More than 80% of the total infused adinazolam dose was converted to systemically appearing NDMAD. All 3 benzodiazepine agonists significantly increased ß EEG activity, with alprazolam showing the strongest agonist activity and adinazolam showing the weakest activity. Alprazolam and NDMAD significantly decreased DSST performance, whereas adinazolam had no effect relative to placebo. Adinazolam, NDMAD, and alprazolam all produced significant observer-rated sedation. Plots of EEG effect versus plasma alprazolam concentration demonstrated counterclockwise hysteresis, consistent with an effect site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect site concentration was related to pharmacodynamic EEG effect via the sigmoid E_max model, yielding an effect site equilibration half-life of 4.8 minutes. The exponential effect model described NDMAD pharmacokinetics and EEG pharmacodynamics. The relation of both alprazolam and NDMAD plasma concentrations to DSST performance could be described by a modified exponential model. Pharmacokinetic-dynamic modeling was not possible for adinazolam, as the data did not conform to any known concentration-effect model. Collectively, these results indicate that the benzodiazepine-like effects occurring after adinazolam administration are mediated by mainly NDMAD.

Key Words: Adinazolam • N-desmethyl adinazolam • alprazolam • electroencephalography • Digit Symbol Substitution Test • pharmacokinetics • pharmacodynamics

Previous studies investigating the pharmacodynamic effects of adinazolam and its active metabolite mainly utilized subjective measures of CNS activity, as well as semi-objective measures of CNS activity, psychomotor performance, and memory.^8,11,12 Computerized analysis of the electroencephalogram (EEG) is recognized as an objective approach to quantitating the CNS effects of benzodiazepine agonists. A number of studies demonstrate that the density of EEG activity in the 13 to 30 cycles/s range closely reflects plasma or hypothetical effect site drug concentration.¹³

In the present study, we examined the pharmacokinetics and pharmacodynamic effects of adinazolam and NDMAD relative to the reference full-agonist benzodiazepine ligand alprazolam. In doing so, we utilized EEG as well as the Digit Symbol Substitution Test (DSST) and subjective, visual analog scales for sedation and mood to quantitate the time course of pharmacodynamic effects of benzodiazepine agonists following intravenous drug administration.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Experimental Procedures
The study protocol was reviewed and approved by the Human Investigation Review Committee serving Tufts University School of Medicine and Tufts-New England Medical Center. Nine healthy Caucasian male volunteers, aged 20 to 40 years (average 29 years), participated in the study after giving written informed consent. All subjects were active ambulatory adults (average weight 80 kg), with no evidence of medical disease and receiving no medications.

Subjects participated in a 5-way blinded crossover study, with at least 1 week elapsing between trials. The first trial (termed a no-treatment trial) was used to evaluate possible adaptation and practice effects on pharmacodynamic rating scales and time-dependent changes in EEG. The no-treatment phase of the study did not involve an intravenous infusion, and blood was not sampled. Electroencephalographic electrodes were affixed according to methods described later in this article. The EEGs were recorded for a period of 5 hours, during which subjects also underwent practice testing with the visual analog rating scales and psychomotor assessments.

The 4 subsequent trials were completed in random sequence with the following treatment conditions: (1) alprazolam, 1 mg; (2) adinazolam mesylate, 10 mg (equivalent to 7.9 mg adinazolam free base); (3) NDMAD mesylate, 10 mg (equivalent to 7.8 mg NDMAD free base); or (4) placebo. Subjects fasted overnight prior to entering the General Clinical Research Center of Tufts-New England Medical Center on the morning of each trial. They ingested a light breakfast approximately 2 to 3 hours before drug administration. Subjects were required to remain fasting for 3 to 4 hours following drug administration, after which they resumed a normal diet. All medications were administered by intravenous infusion into an antecubital or forearm vein. The appropriate dose of active medication or placebo was diluted to 50 mL with physiologic saline and infused by a constant-rate infusion pump over a period of 30 minutes. Intravenous infusions were supervised by the principal investigator, who, for purposes of subject safety, was aware of the treatment condition. However, subjects and study personnel responsible for the EEG monitoring, psychological testing, and blood sampling were unaware of the treatment condition.

Venous blood samples were drawn via an indwelling cannula in the arm contralateral to the site of the infusion prior to dosage and at 0.5, 0.583, 0.667, 0.75, 1.0, 1.25, 1.5, 2.0, 2.5, 3.0, 3.5, 4.5, 5.5, 6.5, 8.5, 10.5, 12.5, and 24 hours following the start of the infusion. Blood samples were centrifuged and the plasma separated and frozen until the time of the assay.

A 5-electrode electroencephalographic montage using bipolar leads was affixed as follows: frontal (Fz), central (Cz), parietal (Pz), and occipital (Oz), with a nose electrode as reference. The EEGs were obtained in 4-second epochs for as long as necessary to ensure at least 2 minutes of artifact-free information. Recordings were taken from each electrode before drug administration and at times corresponding to blood sampling. Data from all electrodes were digitized over the power spectrum from 4 to 30 Hz and analyzed by fast-Fourier transform to determine amplitude in the total spectrum (4-30 Hz) and in the ß frequency range (12-30 Hz).

Subjects' self-ratings of sedative effects and mood state were obtained on a series of 100-mm visual analog scales.^14-16 Ratings of sedation were also performed by a trained observer, with the same rating instrument, without knowledge of the treatment condition. Self-ratings and observer ratings were obtained twice prior to medication administration and at postdosage time points corresponding to EEG recordings.

The DSST was administered twice prior to dosing and at multiple time points after drug administration.^14-16 Subjects were asked to make as many possible correct symbol-for-digit substitutions as possible within a 2-minute period. For each DSST, subjects completed an arbitrarily selected equivalent test variant such that no individual took the same test more than once.

Analysis
Plasma concentrations of alprazolam were determined using gas chromatography with electron-capture detection.¹⁷ The internal standard U-31485 (10 ng, Upjohn Company, Kalamazoo, Mich) was added to study samples and to a series of drug-free calibration plasma samples containing known amounts of alprazolam. Samples were extracted by vortex mixing with toluene/isoamyl alcohol (98.5:1.5). After centrifugation, the organic layer was separated into a 2-mL automatic sampling vial. The solvent was evaporated to dryness at 40°C under mild vacuum. The residue was reconstituted in a mixture of toluene, isoamyl alcohol, and a 1% solution of purified soy phosphatides in toluene (85:12:3). The analytic instrument was a Hewlett-Packard model 5890 gas chromatograph (Hewlett-Packard, Andover, Mass) with a 15-mCi ⁶³Ni electron-capture detector and automatic sampler. The column was coiled glass (1.83 m in length by 2 mm internal diameter), packed with 3% SP-2250 on an 80/100 Supelcort (Supelco, Bellefonte, Pa). The carrier gas was argon-methane (95:5), with a flow rate of 50 mL/min. The operating temperature of the injection port and detector was 310°C and that of the column oven was 275°C. Alprazolam concentrations were calculated using peak-height ratios versus the internal standard. The sensitivity limit of the assay was 1 ng/mL.

Plasma concentrations of adinazolam and NDMAD were determined using high-performance liquid chromatography (HPLC) analysis,¹⁸ with modifications. The internal standard, alprazolam, was added to study samples and to a series of drug-free calibration plasma samples containing known amounts of adinazolam and NDMAD. Samples were extracted 2 times, first with toluene/isoamyl alcohol (98.5:1.5) and second with ethyl acetate. The extracts were combined and evaporated until dryness, and the residue was reconstituted in an HPLC mobile phase, which contained 0.4% (w/v) NH₄H₂PO₄, 11.3% (v/v) CH₃OH, and 24.51% (v/v) CH₃CN. The analytical column was stainless steel, 30 cm by 3.9 mm, containing a reverse-phase C₁₈ µ Bondpak (Waters Associates). The mobile phase flow rate was 1.8 mL/min, and column effluent was monitored by UV absorbance at 220 nm. Adinazolam and NDMAD concentrations were calculated using peak-height ratios versus the internal standard. The sensitivity limit of the assay was 5 ng/mL for each compound.

The relative electroencephalographic ß amplitudes (ß amplitude divided by the total, expressed as a percentage) in the predose recordings were used as baseline values.^14,15,19-21 All values after drug administration were expressed as the increment or decrement over the mean predose baseline value, with values averaged across recording sites.

For self-ratings and observer ratings on visual analog scales, the 2 predose baseline ratings were averaged, and all postdosage scores were expressed as the increment or decrement relative to the mean predose value. Scores on the DSST test were similarly analyzed. Area under the 4.5-hour plot of effect change score versus time was calculated for each pharmacodynamic variable. This is a standard pharmacodynamic procedure to measure effect size.^16,22 The effect area can be either positive or negative, depending on the direction of the change.

Electroencephalographic change values and DSST change scores were subsequently used as pharmacodynamic effect (E) measures in kinetic-dynamic modeling procedures described in the following sections.

Pharmacokinetic Modeling Procedures
For pharmacokinetic modeling, the relation of plasma alprazolam and adinazolam concentration to time was assumed to be consistent with a 2-compartment model. For each subject, the following equation^23-25 consistent with a 2-compartment model was fitted to plasma concentration versus time data using derivative-free nonlinear least squares regression:

(1)

For NDMAD, the selection of model (1 vs 2 compartments) was determined by visual inspection of the plasma concentration versus time data plotted on a log-linear scale. When suitable, the following equation,²³ consistent with a 1-compartment model, was fitted to NDMAD plasma concentration versus time data:

(2)

during the infusion, and

(3)

after the infusion. In equations (1) through (3), T = t when t is <0.5 hours (the infusion duration), T = 0.5 when t is 0.5 hours, and Q is equal to the zero-order infusion rate. For a 2-compartment model (equation (1)), iterated variables are the following: is the apparent hybrid rate constant for the "distribution phase," ß is the hybrid rate constant for the elimination phase, k₂₁ is the intercompartmental transfer rate constant, and V₁ is the apparent volume of the central compartment. For a 1-compartment model (equations (2) and (3)), iterated variables are the following: k is the rate constant for the elimination phase, and V_d is volume of distribution. Residual errors, after squaring, were weighted by the reciprocal of the squared concentration. Iterated parameters from the function of best fit were used to calculate the following values: apparent half-lives of distribution and elimination (t_1/2 and t_1/2ß or t_1/2k, respectively), elimination rate constant (k_e), clearance (CL), and total volume of distribution using the area method (V_d). Data were analyzed for each subject individually.

A model-independent method was used to determine the bioavailability of NDMAD after adinazolam infusion. The fraction of adinazolam that converted systemically appearing NDMAD (F_NDMAD) was calculated according to the following equation:

(4)

where the value of 1.0414 corrects for molecular weight (MW) differences between adinazolam and NDMAD (equal to the MW of adinazolam divided by that of NDMAD).

Kinetic-Dynamic Modeling Procedures
Plasma drug concentrations, as well as electroencephalographic changes and DSST score changes, were averaged across all subjects at corresponding times. The single data set formed by aggregation was analyzed as described in this section.

Examination of plots of pharmacodynamic electroencephalographic effect versus plasma alprazolam concentration (E vs C) indicated counterclockwise hysteresis, consistent with a delay in equilibrium of alprazolam between plasma and the site of pharmacodynamic action in the brain. This has been described in previous clinical and experimental studies with alprazolam and other benzodiazepines.^13,14,26-28 Accordingly, the relationship was modified to incorporate a distinct "effect site" at which the hypothetical alprazolam concentration is C_E. The apparent rate constant for drug disappearance from the effect compartment is k_EO; this rate constant determines the apparent half-life of drug equilibration (t_1/2kEO) between plasma and effect site.^{23,24,27,29,30} The relation of change over baseline in EEG activity and alprazolam C_E was analyzed using the sigmoid E_max model:

(5)

where E_max is the maximum pharmacodynamic effect, EC₅₀ is the value of C_E corresponding to 50% of E_max, and A is an exponent (Hill coefficient). The relation of C_E to time (t) was assumed to be consistent with the following equation:

(6)

In equation (6), T = t when t is <0.5 hours, and T = 0.5 when t is 0.05. Q was fixed as described in equation (1). Values for , ß, k₂₁, and V₁ were fixed as determined from nonlinear regression using equation (1). Using equations (5) and (6) simultaneously, data points (E and t) were analyzed by nonlinear regression. Iterated values were E_max, EC₅₀, A, and k_EO.

The relation of change over baseline EEG activity and NDMAD plasma concentration was analyzed using the following exponential model^25,31:

(7)

Iterated values are as follows: B is a coefficient, and A is an exponent. This model can be viewed as a simplification of the E_max relationship, in which a maximum pharmacodynamic effect is not evident.¹³

Pharmacokinetic-dynamic modeling was also carried out using DSST change scores as a pharmacodynamic measure. The relation of plasma alprazolam and NDMAD concentration to change over baseline DSST (corrected for placebo) was analyzed using the following exponential model modified to incorporate a non-zero baseline performance value^31,32:

(8)

Iterated values are as follows: E₀ is the observed effect with no drug present, B is a coefficient, and A is an exponent.

Statistical procedures include nonlinear regression, analysis of variance, and the Student-Newman-Keuls multiple-comparison procedure.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Figure 1 shows plasma concentrations of adinazolam, NDMAD, and alprazolam following intravenous administration. Plasma adinazolam and adinazolam concentrations were consistent with equation (1), and kinetic variables are presented in Table I. Plasma NDMAD concentrations following intravenous administration in 4 of 9 subjects were consistent with a 1-compartment model (equations (2) and (3)). NDMAD pharmacokinetic variables averaged across all subjects are presented in Table I. In addition, NDMAD was present at detectable concentrations following intravenous adinazolam infusion (Figure 2). Using equation (4), the mean (± SEM) calculated fraction of adinazolam converted to systemic NDMAD (F_NDMAD) was 0.82 ± 0.13.

View larger version (16K): [in this window] [in a new window]   Figure 1. Mean (± SEM) plasma concentrations of alprazolam, adinazolam, and N-desmethyl adinazolam (NDMAD) after intravenous infusion. Respective intravenous doses: 1 mg alprazolam, 10 mg adinazolam mesylate, and 10 mg NDMAD mesylate.

View larger version (13K): [in this window] [in a new window]   Figure 2. Mean (± SEM) adinazolam and N-desmethyl adinazolam (NDMAD) plasma concentrations following intravenous infusion of adinazolam mesylate (10 mg).

Adinazolam, NDAMD, and alprazolam increased EEG activity compared to placebo, but the magnitude of the EEG effect was greatest with alprazolam (Figure 3). NDMAD showed similar maximum activity as alprazolam but was of shorter duration. Adinazolam was a weaker agonist compared to alprazolam and NDMAD. Differences in 4.5-hour effect areas were significant among all treatments.

View larger version (22K): [in this window] [in a new window]   Figure 3. Mean (± SEM) changes over baseline in percent electrographic (EEG)ß amplitude during and after adinazolam mesylate (10 mg), N-desmethyl adinazolam (NDMAD) mesylate (10 mg), alprazolam (1 mg), and placebo infusion. Values represent the increment or decrement over the predose baseline value.

Psychomotor performance testing indicated significant decreases in DSST performance after alprazolam and NDMAD infusion (Figure 4). In contrast, changes in DSST performance after adinazolam infusion were similar to placebo.

View larger version (20K): [in this window] [in a new window]   Figure 4. Scores (mean ± SEM) on the Digit Symbol Substitution Test (DSST) after intravenous infusion of adinazolam mesylate (10 mg), N-desmethyl adinazolam (NDMAD) mesylate (10 mg), alprazolam (1 mg), and placebo. Values represent the increment or decrement over the predose baseline score.

Observer ratings of sedation indicated that alprazolam, NDMAD, and adinazolam have significant agonist activity relative to placebo (Table II). Self-ratings of subjective states based on visual analog scales indicated that alprazolam, the reference full agonist, produced perceptions of being "spacey," sedate, calm, fatigued, peaceful, and irritable; however, differences relative to placebo were not significant. According to area under 4.5-hour effect curves, both NDMAD and alprazolam infusions produced significant perceptions of nervousness, whereas adinazolam produced perceptions of ease.

Plots of plasma alprazolam concentrations versus electroencephalographic change indicated counterclockwise hysteresis. The effect site model eliminated the hysteresis, with a mean t_1/2kEO value of 4.7 minutes (Figure 5). The relation of E to hypothetical C_E was consistent with the sigmoid E_max model, with mean parameters shown in Figure 5. The plot of plasma NDMAD concentrations versus electroencephalographic change indicated no hysteresis. These data were fit to the exponential model, with mean iterated values shown in Figure 6. Plots of plasma alprazolam versus DSST score change and plasma NDMAD concentration versus score change were fit to the modified exponential model, as described by equation (8) (Figures 7 and 8, respectively). The relation of plasma adinazolam concentration to either EEG or DDST did not conform to any effect model.

View larger version (14K): [in this window] [in a new window]   Figure 5. Mean change over baseline in percent ß electroencephalographic (EEG) amplitude (y-axis) in relation to the hypothetical effect site alprazolam concentration (x-axis). The solid line represents the function described by equation (5). Emax, maximum pharmacologic effect; EC50, effect site concentration corresponding to 50% of maximum effect; t1/2kEO, elimination half-life from hypothetical effect compartment; A, an exponent (equation (5)).

View larger version (12K): [in this window] [in a new window]   Figure 6. Mean change over baseline in percent ß electroencephalographic (EEG) amplitude (y-axis) in relation to plasma N-desmethyl adinazolam (NDMAD) concentrations. The solid line represents the exponential function described by equation (7).

View larger version (10K): [in this window] [in a new window]   Figure 7. Relation of plasma alprazolam concentration to change over baseline in Digit Symbol Substitution Test (DSST) score. DSST values are corrected for placebo score. The solid line represents the inhibitory exponential function described by equation (8).

View larger version (10K): [in this window] [in a new window]   Figure 8. Relation of plasma N-desmethyl adinazolam (NDMAD) concentration to change over baseline in Digit Symbol Substitution Test (DSST) score fitted to exponential model. DSST values are corrected for placebo score.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Adinazolam is converted into the active metabolite, NDMAD, after hepatic metabolism.³³ In addition, adinazolam is a CYP3A4 substrate³⁴ and, therefore, may be converted into NDMAD enterically after oral administration. Reported values for oral bioavailability of adinazolam average between 33% and 45%.^11,33 Based on our reported value for adinazolam clearance, the relative contribution of enteric presystemic extraction is substantial. Therefore, intestinal metabolism of adinazolam substantially contributes to incomplete adinazolam oral bioavailability. Previous studies demonstrated that pharmacokinetic parameters for adinazolam and NDMAD can vary with age and across ethnic groups.^6,35 In this study, we demonstrated that pharmacokinetic parameters for adinazolam, NDAMD, and alprazolam in healthy male subjects are similar to those published previously.^9-11

The suitability of electroencephalography as an objective measure of central benzodiazepine agonist effects has been established in many previous clinical and experimental studies.^{14,15,19-21,27,28} Furthermore, electroencephalographic analysis provides quantitative data on the intensity of benzodiazepine agonist activity that is closely correlated with other clinical measures of drug effect (such as sedation, psychomotor performance impairment, and impaired memory).^{13,15,20,21,36-39} In the present study, the pharmacodynamic evaluation of adinazolam, NDMAD, and alprazolam with EEG indicated that alprazolam was the strongest agonist. EEG effects of adinazolam were substantially lower than those of both alprazolam and NDMAD, suggesting that NDMAD might predominantly mediate the pharmacological actions of orally administered adinazolam. When DSST was used as pharmacodynamic measure, alprazolam and NDMAD displayed similar agonist activity, whereas effects of adinazolam were similar to placebo.

In this study, we used both EEG effects and DSST scores as tools to model the pharmacokinetic-pharmacodynamic relationship for adinazolam, NDMAD, and alprazolam, a reference full agonist at the benzodiazepine receptor.

Maximal EEG effects of alprazolam were delayed following intravenous infusion, an effect consistent with a kinetic-dynamic model incorporating a hypothetical effect site distinct from the central compartment. Therefore, the relation between plasma alprazolam concentration and EEG change was best modeled by the sigmoid E_max effect site model, which eliminated the hysteresis. Effect site models have been extensively used to model pharmacokinetic-pharmacodynamic relationships with other intravenously infused benzodiazepine agonists.^28,40,41 In contrast, kinetic-dynamic modeling for plasma NDMAD concentrations and EEG effect revealed little hysteresis. The data were fit to the exponential model, which can be viewed as a simplification of the E_max relationship in which a maximum pharmacodynamic effect is not evident.

Pharmacokinetic-pharmacodynamic modeling for alprazolam using DSST change scores as a pharmacodynamic measure revealed no hysteresis because the first DSST was administered 1 hour after the start of the infusion. Thus, alprazolam plasma concentrations and DSST effects were fitted to the modified exponential model as shown in Figure 7. Similarly, plasma NDMAD concentrations in relation to DSST change scores were also fit to the exponential model, as shown in Figure 8.

Pharmacokinetic-pharmacodynamic modeling was not possible for adinazolam, as the relationship between plasma adinazolam concentration and EEG effect or DSST change score failed to conform to any known effect model. This could be due, in part, to the small magnitude of adinazolam effect relative to the more robust pharmacodynamic effects of alprazolam and NDMAD. After intravenous infusion, more than 80% of adinazolam was systemically converted to NDMAD. However, the actual extent to which adinazolam and NDMAD contribute to adinazolam's benzodiazepine-like effects remains to be elucidated. The net contribution of each agonist depends on the relative affinity of each compound for the benzodiazepine receptor as well as the plasma/brain partition coefficient for each agonist. Overall, the results of this study suggest that adinazolam behaves mainly as a prodrug for NDMAD, and NDMAD is responsible for the majority of the sedative and EEG effects occurring after intravenous adinazolam infusion.

	ACKNOWLEDGEMENTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
This work was supported in part by grants DA-13209, DA-13834, DK-58496, DA-05258, MH-58435, AG-17880, AT-01381 from the Department of Health and Human Services, and by a grant-in-aid from the Upjohn Company. We are grateful for the assistance of the staff of the General Clinical Research Center, Tufts University School of Medicine and Tufts-New England Medical Center (supported by grant RR-00054 from the National Center for Research Resources).

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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