The effect of potent CYP2D6 inhibition on the pharmacokinetics and safety of deutetrabenazine in healthy volunteers.

PURPOSE: Deutetrabenazine is a deuterated form of tetrabenazine with a confirmed lower rate of CYP2D6 metabolism of the active metabolites, α- and ß-HTBZ. In this study, we assessed the effect of paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics and safety of deutetrabenazine and its metabolites. METHODS: In this open-label sequential drug-drug-interaction study, 24 healthy adults who were CYP2D6 extensive or intermediate metabolizers received a single deutetrabenazine 22.5-mg oral dose on days 1 and 11 and a single paroxetine 20-mg oral daily dose on days 4-12. Pharmacokinetics of deutetrabenazine and its metabolites were assessed on days 1-4 and 11-14. Paroxetine trough concentrations were obtained pre-dose on days 9-13. Safety examinations occurred throughout the study. RESULTS: Paroxetine administered under steady-state conditions, increased exposure of the deuterated active metabolites, α-HTBZ (1.2-fold Cmax and 1.8-fold AUC0-∞) and ß-HTBZ (2.1-fold Cmax and 5.6-fold AUC0-∞), and correspondingly, 1.6-fold Cmax and threefold AUC0-∞ for total (α + ß)-HTBZ. Sixteen subjects reported 45 adverse events and most were mild. Headache was the most common AE reported 8 times by 7 subjects (5 following paroxetine alone; 2 following deutetrabenazine + paroxetine). CONCLUSIONS: Paroxetine-induced increases in exposure to the active deutetrabenazine metabolites were less than those previously reported for tetrabenazine, a finding expected to reduce the burden of drug interaction. In addition, single doses of 22.5 mg deutetrabenazine, when given alone or in the presence of steady-state paroxetine (20 mg daily), were safe.

The effect of mild and moderate renal impairment on the pharmacokinetics of pridopidine, a new drug for Huntington's disease.

AIM: Pridopidine, a new oral drug for treatment of patients with motor symptoms associated with Huntington's Disease (HD) is currently under development. In steady-state conditions, pridopidine elimination is mediated primarily through renal excretion. This study evaluated single dose and steady-state pharmacokinetics (PK) of a daily dose of pridopidine in subjects with mild and moderate renal impairment and matched healthy subjects. METHODS: Subjects with mild renal impairment (n = 12), moderate impairment (n = 12), or their matched healthy controls (n = 25) participated in this study. Subjects received a single dose of pridopidine (45 mg) on day 1 and a multiple dose cycle of 45 mg once daily on days 5-18. Blood and urine samples were collected on days 1 and 18 for PK analysis. RESULTS: Mild renal impairment did not affect the PK of pridopidine whilst an increase in exposure was seen in subjects with moderate renal impairment. Subjects with moderate impairment showed reduced plasma clearance (by 44%) and had 68% higher AUC (90% CI 1.22, 2.30) and 26% higher Cmax (90% CI 1.02, 1.56) values than those with normal renal function at steady-state. Pridopidine was safe and well tolerated in healthy subjects and in subjects with mild and moderate renal impairment. CONCLUSIONS: Mild renal impairment has no impact on exposure to pridopidine while moderately impaired renal function resulted in higher pridopidine concentrations.

Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions: an in vivo study in rabbits.

PURPOSE: To evaluate and compare the toxicological profiles of two quaternary ammonium compounds (QAC), benzalkonium chloride (BAK), and cetalkonium chloride (CKC), in standard solution or cationic emulsion formulations in rabbit eyes using newly developed in vivo and ex vivo experimental approaches. METHODS: Seventy eyes of 35 adult male New Zealand albino rabbits were used in this study. They were randomly divided into five groups: 50 microl of phosphate-buffered saline (PBS), PBS containing 0.02% BAK or 0.002% CKC (BAK Sol and CKC Sol, respectively), and emulsion containing 0.02% BAK or 0.002% CKC (BAK Em and CKC Em, respectively) were applied to rabbit eyes 15 times at 5-min intervals. The ocular surface changes induced by these eye drops were investigated using slit-lamp examination, flow cytometry (FCM), impression cytology (IC) on conjunctiva, and corneal in vivo confocal microscopy (IVCM). Standard immunohistology in cryosections was also examined for cluster of differentiation (CD) 45+ infiltrating and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL)+ apoptotic cells. RESULTS: Clinical observations and IVCM showed that the highest toxicity was induced by BAK Sol, characterized by damaged corneal epithelium and a high level of inflammatory infiltration. BAK Em and CKC Sol presented moderate effects, and CKC Em showed the lowest toxicity with results similar to those of PBS. Conjunctival imprints analyzed by FCM showed a higher expression of RLA-DR and TNFR1 markers in BAK Sol-instilled eyes than in all other groups, especially at 4 h. Immunohistology was correlated with in vivo and ex vivo findings and confirmed this toxicity profile. A high level of infiltration of CD45+ inflammatory cells and TUNEL+ apoptotic cells was observed in limbus and conjunctiva, especially in QAC solution-receiving eyes compared to QAC emulsion-instilled eyes. CONCLUSIONS: The acute administration of 15 instillations at 5 min intervals was a rapid and efficient model to assess quaternary ammonium toxicity profiles. This model showed the highest toxicity, induced by the BAK solution, and the lowest level of toxicity, induced by the CKC emulsion. These in vivo and ex vivo experimental approaches demonstrated that ocular surface toxicity was reduced by using an emulsion instead of a traditional solution and that a CKC emulsion was safe for future ocular administration.