Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of...
A common viewpoint has proliferated that cannabis use is mostly harmless. Some argue that by not supporting its use, we are missing a great therapeutic opportunity. The general public view on cannabis may partially be a result of poor knowledge translation. In fact, the “war on drugs” approach has not allowed for basic education on the varied effects of cannabis on the brain, especially at...
Clearance of atorvastatin occurs through hepatic uptake by organic anion transporting polypeptides (OATPs) and subsequent metabolism by cytochrome P450 (CYP) 3A4. To demonstrate the relative importance of OATPs and CYP3A4 in the hepatic elimination of atorvastatin in vivo, a clinical cassette microdose study was performed. A cocktail consisting of a microdose of atorvastatin along with probe...
This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at...
In this issue, Hysek and colleagues present new data describing the impact of treatment with reboxetine on the effects produced by 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in human volunteers. They demonstrate that several effects of MDMA are mediated by reboxetine's actions on norepinephrine (NE) transporters, an unexpected finding. Building on earlier work, their new data provide...
Microdosing studies are effective in enabling the early identification of the pharmacokinetic properties of compounds administered to humans. However, the nonlinearity of the pharmacokinetics between microdose and therapeutic dose, attributable to the saturation of metabolic enzymes and transporters, is a major concern. Verapamil and quinidine are good substrates of both the multidrug...
This study assessed the pharmacodynamic and pharmacokinetic effects of the interaction between the selective norepinephrine (NE) transporter inhibitor reboxetine and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in 16 healthy subjects. The study used a double-blind, placebo-controlled crossover design. Reboxetine reduced the effects of MDMA including elevations in plasma levels of NE,...
Sativex is a cannabis-plant extract delivering nearly 1:1 Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4...
The Food and Drug Administration (FDA) Critical Path Initiative as well as the European Medicines Agency Road Map to 2010 (ref. 2) call for opportunities for more efficient drug development. One of the initiatives that has emerged in this context is the elaboration through guidance of exploratory investigational new drugs (INDs)/clinical trial applications (CTAs). This article reviews the...
OBJECTIVES: A volunteer trial was performed to compare the pharmacokinetics of 5 drugs--warfarin, ZK253 (Schering), diazepam, midazolam, and erythromycin--when administered at a microdose or pharmacologic dose. Each compound was chosen to represent a situation in which prediction of pharmacokinetics from either animal or in vitro studies (or both) was or is likely to be problematic. METHODS: In...
ObjectiveWe investigated the pharmacokinetics of ketamine with special regard to enantiomer‐specific differences.MethodsTen healthy young male volunteers (mean age, 28 ± 4 years; mean weight, 79 ± 11 kg) received racemic ketamine and S(+)‐ketamine in a randomized double‐blind crossover study. Drugs were administered by a computer‐controlled device. Two infusion cycles with linearly increasing...
Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)-ketamine were measured in a randomized, double-blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous...
Rapid blood collection, a paced smoking protocol and timely collection of physiologic and behavioral measures were used to characterize the absorption phase of marijuana smoking. Six healthy males smoked a single marijuana cigarette (placebo, 1.75%, or 3.55% delta-9-tetrahydrocannabinol) in a double-blind, randomized, Latin square study design. Rapid blood sampling with a continuous withdrawal...
Oral doses of delta-9-tetrahydrocannabinol (THC) 20 mg, combined with placebo or with 40 mg dses of cannabinol (CBN) and cannabidiol (CBD), were given to volunteers. The combination of THC with CBN produced no detectable changes in the quality, intensity, or duration of the effects of THC alone. The THC-CBD combination tended to delay onset and prolong effects of THC, while making them somewhat...
A synthetic isomer of tetrahydrocannabinol (1‐Δ'‐3,4‐transtetrahydrocannabinol), believed to be identical to the most active naturally occurring THC, was compared with a semisynthetic THC‐like compound, synhexyl. Sixteen volunteer subiects received THC in doses ranging from 341 to 946 p.g per kilo gram (median 581). Thirteen subjects received synhexyl in doses ranging from 633 to 2,666 µg per...
Previously published plasma concentrations of LSD‐25, observed following intravenous iniection of 2 mcg. per kilogram of LSD‐25, have been found to be explained by the two‐compartment open model. Performance scores on arithmetic tests were shown to be highly linearly correlated with the concentration in the “tissue” (outer) compartment. The estimated volume of the plasma (inner) compartment was...
This is a review of an important but controversial subject, written by one of the important figures involved in the controversy. It was not possible to get a review in depth by someone who was not also involved in the controversy. With this in mind, this review was accepted for publication because it was written by an authority actively engaged in the problem and because it was thought...
Two micrograms per kilogram of LSD‐25 was administered intravenously to five normal human subjects. The concentration of drug in plasma was determined serially over the subsequent 8 hours. LSD‐25 was found to be present in human plasma in relatively large quantities during the period of peak effect. The half‐life of LSD‐25 in human plasma was calculated to be 175 minutes.