Pharmacokinetics of AR19, an Immediate-Release Amphetamine Sulfate Formulation Designed to Deter Manipulation for Administration Via Nonoral Routes: Bioequivalence to Reference Racemic Amphetamine Sulfate, Dose Proportionality, and Food Effect

Abstract

Objectives: We evaluated the pharmacokinetics (PK) of an investigational immediate-release amphetamine (AMP) sulfate formulation (AR19) designed to deter nonoral administration versus reference racemic amphetamine sulfate (RA-AMPH). We investigated AMP bioavailability from AR19, the effect of taking AR19 with food or sprinkling the capsules on food, and dose proportionality. Methods: Participants received AR19 (20 mg) or reference RA-AMPH (20 mg) (bioequivalence study) or AR19 5 or 30 mg (dose comparison study). Food effect study participants received AR19 (20 mg) as intact capsule while fasted or after highfat/-calorie meal, or as pellets sprinkled on applesauce or yogurt ( ‡6-day washout). Blood samples were analyzed for dextroamphetamine (d-AMP) and levoamphetamine (l-AMP) PK: C max , AUC last , AUC inf , k z , T ½ , and T max . Safety was assessed. Results: Bioequivalence, dose comparison, and food effect studies included 36, 24, and 36 participants. The 90% confidence intervals (CIs) of C max , AUC last , and AUC inf for AR19 20 mg versus reference RA-AMPH or AR19 with intact capsule and meal or sprinkled AR19 pellets on food versus fasted were between 80% and 125%. Dose-normalized C max /D, AUC last /D, and AUC inf /D for AR19 5 versus 30 mg had CIs within 80%-125%. Meanstandard deviation (SD) T max was comparable for AMP (d-AMP; l-AMP) following AR19 20 mg (2.84 -1.05; 3.05 -1.22) versus reference RA-AMPH (2.52 -0.75; 2.75 -1.00), and AR19 5 mg (2.48 -0.57; 2.65 -0.65) versus AR19 30 mg (2.55 -0.56; 2.72 -0.65). Mean -SD T max for AMP (d-AMP; l-AMP) was higher with intact capsule and meal (5.59 -1.57; 5.59 -1.59) versus fasted (2.85 -0.76; 2.97 -0.79). No serious adverse events were reported. Conclusion: AR19 was bioequivalent to reference RA-AMPH. Bioavailability was similar at doses between 5 and 30 mg and was not impacted by meal consumption or sprinkling on food. AR19 at tested doses was well tolerated.

Chiral pharmacokinetics of tetramisole stereoisomers—Enantioselective quantification of levamisole and dexamisole in serum samples from users of adulterated cocaine

“…As already observed with the forensic serum samples, also in this experiment, higher concentrations of dexamisole than of levamisole are present at all time points. This is in contrast to observations for amphetamine 43,46 and 4‐FA, 17 where (R)/(S)‐ratios <1 were observed in the absorption phase. On the other hand, for MDMA, (R)/(S)‐ratios were >1 at any time as well 16,41,42 .…”

Enantioselective Quantification of Amphetamine and Metabolites in Serum Samples: Forensic Evaluation and Estimation of Consumption Time

“…The amphetamine (R)/(S) ratios calculated in the sample collective are consistent with the use of racemic amphetamine, taking into account the shorter elimination half-life of (S)-amphetamine [ 28 , 29 ]. The median (R)/(S) ratio in this study was 1.11, which was significantly lower than the median of 1.69 found by Hess et al in a similar study (n = 28) [ 35 ].…”

“…Moreover, in a controlled oral intake study by Wan et al (10 mg racemic amphetamine, n = 4), (R)/(S) ratios ranging from 0.84 to 1.18 were observed during the absorption phase [ 29 ]. The occurrence of (R)/(S) ratios below 1.00 is also supported by the studies of Caras and Sharpe, which found higher mean peak serum concentrations of (S)-amphetamine while the times of peak serum concentrations of both enantiomers were similar [ 28 ]. Furthermore, in a study with controlled oral intake of racemic 4-fluoroamphetamine (4-FA), (R)/(S) ratios below 1.00 were observed during the absorption phase (partially even beyond) [ 36 ].…”

“…Using the serum half-lives determined by Caras et al (oral intake of 30 mg racemate) of 13.4 and 10.8 h for (R)- and (S)-amphetamine, respectively [ 28 ], slopes of 0.015 and 0.020 h −1 are obtained over 24 and 72 h, respectively. In this context, it should be noted that the theoretical slope of the (R)/(S) ratios increases with time, and the linear fit is thus an approximation.…”

“…Studies suggest an approximately 3–4-fold higher efficacy of the (S)-enantiomer [ 26 , 27 ]. Studies further demonstrate stereoselective metabolism of amphetamine, with preferential elimination of the (S)-enantiomer [ 28 , 29 , 30 ]. In the human body, amphetamine is metabolized to norephedrine and 4-hydroxyamphetamine.…”