Backing a winner

Bringing a drug to market has been likened to betting on a horse race - implementing a data driven strategy early in clinical development could mean you back the odds on favourite 

The pharmaceutical industry and the innovative individuals within it are looking closely at how preferred drug candidates move into the clinic. New development strategies which are emerging as commercial and scientific drivers, together with a more flexible regulatory environment, are challenging the traditional route of Phase I – II – III clinical trials.
 
A detailed analysis by the FDA (Food and Drug Administration) of new drug submissions between 1995 and 2005 identified four main underlying causes of the current poor productivity in the industry. This led to the introduction of the Critical Path Initiative. Regulators, academia and pharmaceutical companies have come together under this banner to address the lack of good lead compounds and the high number of drugs in development that fail late in the process.

Incorporating new technology into initial clinical studies can address ‘developability’ issues much earlier in the drug development programme, pre-empting possible shortcomings of a lead compound and informing key Go / NoGo decisions.

Figure 1: Flexibility and dosing options within a single ascending dose protocol

A schematic that represents a typical single ascending dose (SAD) safety, tolerability and pharmacokinetic First-in-Man (FIM) study that might be completed by Pharmaceutical Profiles at its purpose-built facilities in Nottingham, UK, is shown in Figure 1.

This two stage protocol, with appropriate decision algorithms and stopping rules, allows the introduction of treatment options designed to utilize the safety and pharmacokinetic information obtained in the first part of the study. These might include:

• Minor changes in dose in order to more precisely define the maximum tolerated dose.
• Evaluation of the effect of food on drug bioavailability.
• Administration by a different administration route to assess options to improve or alter the pharmacokinetic profile.
• Administration of a different formulation to assess prototype formulations or delivery options.
• The introduction of a second subject population to evaluate potential effects of gender or age on the pharmacokinetics or safety profile of the candidate drug.
 
Key factors in being able to build flexibility into studies include the ability to develop new dosage forms quickly, and to be able to manufacture and release them for use in the clinic on the day of the study, so avoiding the need to perform lengthy stability testing. To do this, a single facility must have full GMP (Good Manufacturing Practice) and GCP (Good Clinical Practice) accreditation. Pharmaceutical Profiles has achieved this status and is ideally placed to offer its clients this service for most formulation types - IV, oral and inhaled, for example. 

Below are two examples where extemporaneous dose manufacture and flexible design have been accommodated within Phase I study protocols.

Adverse events associated with Cmax: Simulated controlled-release delivery.
 
Pharmacologically-based adverse events (AEs) were associated with peak plasma concentrations in preclinical studies with a novel CNS compound. Detection of Cmax associated AEs in Part A of the SAD FIM study triggered an option to administer the maximum tolerated dose (MTD) as a number of different divided doses. This would establish the feasibility and potential for modified or sustained-release delivery of this drug.

This was a two-part, single ascending dose, safety, tolerability, pharmacokinetic and pharmacodynamic study. Part A was designed to establish the MTD; eight subjects were used for each dose increment; Part B was designed to allow administration of the drug as three divided dose regimens.

Figure 2: Mean profiles for drug given as:60mg single oral dose 200mg oral divided dose over 12 hours

Part A defined the MTD at 60mg. AEs associated with the pharmacological action were observed at doses above 60mg, in a dose-related manner.
Pharmacokinetic simulation, based on the ascending dose profiles, indicated that a 200mg dose administered over 3, 6 or 12 hours would reduce the Cmax and associated AEs.

Part B was successfully completed using the divided dose regimens. The data for both the delivery as a single oral dose and the divided dose over 12 hours are shown in Figure 2.

Incorporation of flexibility into this study was only made possible by adopting procedures for the extemporaneous GMP manufacture of the active pharmaceutical ingredient (API). Dividing the maximum dose has demonstrated the potential for a modified release delivery of this drug in order to minimise Cmax associated AEs.

Issues with short half-life: potential for controlled release delivery if the drug is absorbed from the colon.

The target product profile was for a once daily oral drug for the treatment of
Rheumatoid Arthritis / Osteo Arthritis. Once daily dosing usually implies a half-life in excess of 4 hours, depending upon the therapeutic window. Preclinical data for this drug indicated that the half-life in man may be less than 3 hours and therefore once daily dosing may not be possible. There were also solubility and dissolution data to indicate a potential for poor in vivo dissolution at therapeutic doses.

Dosing Regimen	Mean AUC (ng.hr/mL)	Frel (%)
IR reference	2.84
Colon-particulate	0.22	8
Colon-solution	2.78	98

This was a two part single ascending dose, safety, tolerability, pharmacokinetic and regional absorption study. Part A was designed to establish the MTD and describe the pharmacokinetic characteristics of the drug. Part B was designed as a three way crossover to quantify the bioavailability of the drug at the MTD administered directly into the colon as a solution and a particulate form in comparison with the immediate release formulation.

Part B would only take place if the drug half-life determined in Part A was less than 4 hours. Administration of the drug to the colon as a solution and particulate form was achieved using Pharmaceutical Profile’s patented Enterion capsule technology.

Part A of the study showed the drug to have a half-life of 2-3 hours. This was not considered to be suitable for once daily dosing and therefore Part B of the study was initiated.

Using the Enterion capsule, the drug was administered directly into the colon as a particulate form. Under these conditions, it showed a reduced bioavailability of ~8% in comparison with the oral immediate release formulation. However, when the same dose was administered directly into the colon as a solution the relative bioavailability increased to approximately 98% (Figure 2).

Incorporation of a flexible, two part study design, based on existing knowledge of potential bioavailability issues, has provided evidence that this drug could be adequately absorbed form the colon and that a modified release formulation would be possible provided adequate in vivo solubilisation is achieved.

Developing an early knowledge of the physicochemical, preclinical safety, ADME, pharmacology and formulation characteristics of a lead compound in humans can identify potential ‘developability’ issues.

The use of flexible study protocols, through the application of new technologies such as Enterion, and the ability to accommodate extemporaneous GMP manufacture, for example, adds considerable value to the early clinical development of new molecules

A consensus is growing, that applying such a data-driven strategy early in clinical development can help reduce late attrition rates.

Dr Karen Jones is Vice President, Marketing for Pharmaceutical Profiles, specialists in early clinical drug development.