Single Oral Dose Safety, Tolerability, and Pharmacokinetics of PNU‐96391 in Healthy Volunteers

Abstract

The safety, tolerability, and pharmacokinetics of PNU-96391, an orally active weak dopamine D2 receptor antagonist with modulatory properties of central dopaminergic function, was characterized. Fifty-three healthy normal volunteers were enrolled in this randomized, double-blinded, placebo-controlled, single-dose study. Subjects were assigned to single oral doses of placebo and 1, 3, 10, 30, 100, 150, and 200 mg PNU-96391. Safety and tolerability were assessed using telemetry, Holter monitoring, surface ECG, vital signs, safety laboratories, and adverse event reports. Pharmacokinetic parameters were determined by model-independent techniques. Adverse events were infrequent, of mild to moderate intensity, and in the dose range of 1 to 150 mg. Dose escalation was stopped at 200 mg because of severe nausea, dizziness, lightheadedness, and tachycardia. Besides the increase in heart rate, no other drug-related effects on vital signs were observed. Safety laboratory measurements were not significantly changed. Evidence of drug activity was demonstrated by a dose-dependent elevation in serum prolactin. PNU-96391 was rapidly absorbed, with maximum concentrations achieved between 0.5 and 4 hours in all subjects. The half-life of the drug was short (2 to 6 h). The main metabolite, PNU-100014, was rapidly formed, with a t(max) ranging from 1 to 6 hours. Peak levels of the metabolite are approximately half of the parent drug, and the half-life is slightly longer (4 to 10 h). Increases in dose resulted in linear increases in exposure for both PNU-96391 and PNU-100014. Hence, PNU-96391 was well tolerated at doses ranging from 1 to 150 mg.

The Dopamine Stabilizer (−)-OSU6162 Occupies a Subpopulation of Striatal Dopamine D2/D3 Receptors: An [11C]Raclopride PET Study in Healthy Human Subjects

“…In contrast to this apparent plateauing of striatal D2/D3 receptor occupancy, plasma prolactin levels increased linearly with ( À )-OSU6162 plasma concentrations (Figure 1), which is in agreement with a previous study (Rodriguez et al, 2004). It is likely that this reflects an antagonistic action of ( À )-OSU6162 on pituitary dopamine D2 receptors, which in the intact system mediate tonic inhibition of prolactin release.…”

“…Subsequent doses were chosen based on the outcomes of the previous PET scans in the current study. The maximum dose was set to a clinically safe and relevant dose of 90 mg, well below the previously observed maximally tolerated dose of 150 mg (Rodriguez et al, 2004). The study had been approved by the Medical Ethics Review Committee of the VU University Medical Center Amsterdam.…”

“…Single oral doses of ( À )-OSU6162 up to 150 mg appeared safe and well tolerated. ( À )-OSU6162 plasma levels were reported to reach peak values (T max ) at 1-1.5 h (Rodriguez et al, 2004).…”

“…In vivo, however, it appears to be an antagonist devoid of intrinsic activity over a wide range of doses (Carlsson et al, 2011;Rung et al, 2011). Evidence in humans of a dopamine D2 antagonistic action of ( À )-OSU6162, at the level of the pituitary, was demonstrated indirectly by a dose-dependent elevation in serum prolactin (Rodriguez et al, 2004). Although ( À )-OSU6162 also demonstrates affinity for serotonergic 5-HT1 and 5-HT2 receptors, in both cases acting as a partial agonist (Burstein et al, 2011;Carlsson et al, 2011), and for sigma sites (Sahlholm et al, 2013), especially its effects on the dopamine system have been well characterized.…”

Tolerability and efficacy of the monoaminergic stabilizer (−)-OSU6162 (PNU-96391A) in Huntington’s disease: a double-blind cross-over study

“…An interesting notion concerning the possible presence of a pharmacological carry-over effect mentioned earlier, is that (−)-OSU6162 may have beneficial effects on plasticity, given that the half-life of this compound is only about 4 h (27). Apparently such an effect is exerted by pridopidine, given the slow development, during several months, of the action of that compound on motor functions.…”