As part of the phase 1 clinical trial program for a new drug, a single dose of the drug is given to healthy volunteers and blood samples are taken at regular intervals to establish plasma drug concentrations (Cp).  The decrease in Cp over time is shown in the graph below. 

Based on this, which of the following predictions could be made about this new drug? It is:

In pre-clinical studies, Eli Lilly tested four lead compounds for efficacy as selective serotonin reuptake inhibitors, using both in vitro and in vivo assays in rodents.

Initial studies investigated in vitro efficacy and selectivity.

Table 1: Assessment of in vitro efficacy of lead compounds in rodents

Inhibition of 5-HT uptake was assessed using synaptosomal preparations of rat brain, and affinity of binding to α₁-adrenoceptors was assessed using membrane preparations of rat cerebral cortex.

IC₅₀ = half maximal inhibitory concentration

In pre-clinical studies, Eli Lilly tested four lead compounds for efficacy as selective serotonin reuptake inhibitors, using both in vitro and in vivo assays in rodents.

Initial studies investigated in vitro efficacy and selectivity.

Table 1: Assessment of in vitro efficacy of lead compounds in rodents

Inhibition of 5-HT uptake was assessed using synaptosomal preparations of rat brain, and affinity of binding to α₁-adrenoceptors was assessed using membrane preparations of rat cerebral cortex.

IC₅₀ = half maximal inhibitory concentration

During lead optimisation, all lead compounds were evaluated for carcinogenic effects using the Ames test.

Table 3:  Assessment of growth of his- salmonella in histidine free media in the absence or presence of liver extract.

++ = colony growth

Based upon the data shown in Table 3, which of the following compounds, together with its metabolites, has mutagenic potential?

Codeine produces analgesia primarily after being metabolised

to morphine by the liver enzyme CYP2D6. Genetic variation can result in

differences in the number of functional copies of the CYP2D6 gene, altering

enzyme activity.

In a patient who carries an additional functional copy of

the CYP2D6 gene, which outcome is MOST LIKELY following standard doses of

codeine?

A researcher is choosing between a cell-based (in vitro

)

assay and a whole-organism (

Which type of information is MOST LIKELY to require an

in

vivo

Paclitaxel is a cytotoxic chemotherapy drug being tested in

early clinical trials for its capacity to treat cancer. Phase I trials are

designed primarily to assess safety, tolerability, and dosing, rather than

efficacy.

Based on the goals of Phase I trials and the disease being targeted,

which population is MOST LIKELY to have been used initially?

A drug development program involves a series of decisions,

where each stage must generate sufficient evidence to justify the cost, risk,

and regulatory requirements of the next stage. Some activities can only occur

once earlier scientific uncertainties have been resolved.

Codeine is a prodrug that requires metabolic conversion by

the liver enzyme CYP2D6 to form morphine, which is responsible for most of its

analgesic effect. Some drugs and genetic variants reduce or inhibit CYP2D6

activity.

If CYP2D6 activity is inhibited in a patient taking codeine,

what outcome is MOST LIKELY with respect to pain relief?

In 2006, TGN 1412, a super-agonist antibody targeting the

immune system, was administered to six healthy volunteers in a Phase I clinical

trial. Unexpectedly, the drug triggered a cytokine storm, leading to

multi-organ failure.

Considering what is known about pre-clinical testing and

species differences, which explanation MOST LOGICALLY accounts for why this

severe immune toxicity was not predicted before human trials?