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International Clinical Trials

Poorly Soluble Drugs

John McDermott of Quotient Bioresearch discusses the impact of poor drug solubility on bioavailability and strategies to develop and clinically validate enabled formulations in humans

High-throughput drug discovery, while efficient for identifying promising compounds, has resulted in a larger number of poorly soluble drugs entering the pipeline for development. It is estimated that 70 per cent of the new chemical entities (NCEs) entering drug development programmes have insufficient aqueous solubility to enable adequate and consistent gastrointestinal (GI) absorption to ensure efficacy (1).

Solubility can be studied on the bench or in preclinical models, but the full impact of the potential bioavailability problem is not fully understood until the molecule is administered to humans. If the resultant clinical data indicates solubilitylimited absorption, the need to transition the development plan to a formulation that maximises solubility and delivers a concomitant increase in exposure becomes a critical path activity. Key to the success of this transition is the ability to rapidly screen prototype formulations in humans to validate the potential enhancement of bioavailability.

REVIEWING THE SITUATION

To be effective, a solid oral dosage form must disintegrate, and the drug loaded into the dose must dissolve, be absorbed and enter the systemic circulation. The rate of absorption of the drug, and hence its exposure, is linked to the intrinsic dissolution rate, which is affected by properties such as crystallinity and hydrophobicity; and the inherent solubility of the drug molecule, which is driven by factors embedded within the chemical structure, such as the number of ionisable groups and molecular weight.

While these characteristics can be studied on the bench through standard pre-formulation measurements and dissolution studies, the full impact can only be truly assessed once the molecule is administered to a human subject. When the molecule is first administered to a human, usually as part of the single ascending dose study, the solubility problem is confirmed. The data may show low and variable bioavailability, extended Cmax, nonlinear pharmacokinetics (PK) and a susceptibility to food effect.

To overcome these bioavailability problems, the development team must address the solubility problem using an enabled formulation, and then validate the performance of the new drug product in a further clinical study with a minimal loss of time.

OVERCOMING SOLUBILITY ISSUES

The development team has two general options to address solubility problems: API modifications and formulation technology. API modifications may include salt selection and polymorphism studies and cover particleengineering approaches such as nanotechnology. These approaches seek to improve solubility through reducing the crystallinity within drug particles and increasing surface area. Formulation technologies include amorphous solid dispersions and liquid systems, such as lipid and surfactant systems. These methods aim to enhance solubility through an improvement in intrinsic dissolution rate or by modifying the local environment around the dosage form.

Formulators can call on these technologies to develop prototype formulations that can be characterised in the laboratory using conventional analytical techniques such as dissolution studies. These techniques are entirely appropriate in formulation development studies. However, because of the relative simplicity of these models, successful prototype formulations must subsequently be tested in the clinic to confirm that the solubility limitations have been overcome.

PRECLINICAL & CLINICAL ASSESSMENT OF PROTOTYPE FORMULATIONS

Traditionally, laboratories screen formulations to assess multiple prototypes in preclinical species in order to identify a limited number of lead systems, which can then enter a human clinical PK study (see Figure 1). Assessments have indicated this process can cost in excess of $1 million and take more than 12 to 15 months.

The problem, however, is that no animal model corresponds completely to human subjects, and such data cannot be used as surrogates for clinical results. Table 1 shows parameters that affect the dissolution and absorption process in preclinical and human models including intestinal pH, transit time and fluid compositions (2,3). Figure 1 shows that studies of the use of animal models in predicting human bioavailability have indicated substantial inter-species physiological differences, including dissolution of the dosage form (4). As such, exposure enhancements observed in preclinical testing may not be reflected in human studies, and therefore a further cycle of in vitro and in vivo studies is required, causing additional delays to the development programme. 

Table 1: Comparison of dog and human gastrointestinal system  
  Human
 Dog
 Intestinal pH
5.5-6.8
6.5-8.0
 Small intestine transit
Mean 238 minutes (range 180 to 300 minutes)
 Mean 11 minutes (15 to 206 minutes)
 Bile acid concentration (fasted state)
 2mM  6mM
 Phospholipid concentration (fasted state)
 0.2mM  2mM
 Neutral lipid concentration
 0.1mM 3mM

RAPID FORMULATION DEVELOPMENT & CLINICAL TESTING

The industry requires a more time and cost-effective approach that offers the advantages of greater flexibility, precision and consequently higher probability of success. The emergence of rapid formulation development and clinical testing (RapidFACT) strategies has been built on two principles: the desire to screen formulation prototypes based on human PK data rather than from non-representative preclinical models; and the need to expedite chemistry, manufacturing and controls (CMC) activities by enabling screening of prototype formulations in humans (see Figure 2).

By integrating development, manufacturing (GMP) and clinical (GCP) facilities, laboratories can remove inherent inefficiencies and move non value-added activities such as manufacture scale-up and up-front generation of ICH stability data off the critical path to generate human PK data.

These strategies integrate formulation development, drug product manufacture and clinical testing to optimise drug development. Candidate formulations can be rapidly screened, selected and validated on the basis of their performance in humans – thereby improving the chances of identifying a drug product that can achieve the target product profile. This approach creates a rapid and seamless manufacturing-to-clinic transfer of drug products up to 24 hours before dosing.

The ability to manufacture on a small scale can conserve drug substance – often a critical factor in early development. With integrated GMP/GCP facilities, a manufacturer can assign a nominal shelf-life of three to seven days to allow for batch release prior to clinical dosing. As a result of this efficiency, the CMC regulatory requirements for drug products can be simplified as follows:

  • Reduced end-product testing (for example, assay, purity and dissolution testing)
  • No microbiological testing
  • Reduced stability data (for example, up to seven days at controlled ambient (15-25ºC) and refrigerated conditions (2-8ºC) given the limited shelf-life required)

CLINICAL STUDY DESIGN & DELIVERY

Short manufacturing cycle times offer several advantages in the clinical execution of formulation optimisation studies. Specifically, real-time manufacturing can enable flexibility to be introduced in the clinical protocol. Integrated GMP/GCP processes allows clinical data from one dosing period to drive the real-time manufacture and dosing of the next prototype formulation within a 10- to 14-day cycle. This allows a selection of the optimal drug product to be completed in a few weeks amongst the same group of healthy volunteers, thereby improving the accuracy of the decision-making process. The careful selection of which dosage form to make and test can enhance efficiency in the study and maximise the value of each study period.

An example of how these programmes can accelerate the process of switching to an enabled formulation is shown in Figure 3. Phase I clinical studies on the molecule in question showed significant variability in the fasted state, nonlinear PK and a pronounced, positive food effect. In this case, the challenge was to find an oral formulation rapidly, ideally in a solid dosage form, which overcame the observed PK variability in the fasted state and the mentioned food effect.

The development team chose to mimic the food effect seen with the existing formulation by delivering the drug using a lipid-based, liquid-filled capsule formulation. In the development programme, excipients and prototype formulations were studied to evaluate physical and chemical compatibility and stability. The resulting prototypes were screened through a discriminatory dissolution test using neat API and the existing instant release (IR) formulation as references. Finally, a series of demonstration batches of candidate formulations were manufactured in accordance with GMP to provide CMC data for submission to the UK regulatory authority. Approval to commence recruitment for the clinical study was received in 14 days.

The candidate formulations were then dosed to 10 healthy volunteers who had fasted. The three lipid-based formulations demonstrated relative bioavailabilities (Frel) of 78 to 96 per cent upon fasted administration, when compared with the IR formulation dosed in the fed state. When the lead formulation was studied in the fed state in a fifth dosing period, it was confirmed that the food effect of the original formulation was overcome. The timeline was 16 weeks from the first prototype formulation to the final version. The total project duration for this clinical trial was 26 weeks.

CONCLUSION

Poor solubility in drug candidates, while increasingly prevalent, can be addressed more effectively than conventional development approaches allow. Screening formulation prototypes using the RapidFACT paradigm reduces the impact upon the development programme, decreases risks and facilitates the transition to an optimised formulation. By addressing the solubility challenge upon bioavailability in early development companies have the ability to benefit from significant time and cost savings.

References

1. Gursoy RN and Benita S, Self-Emulsifying Drug Delivery Systems (SEDDS) for improved oral delivery of lipophilic drugs, Biomed Pharmacother 58(3): pp173-182, 2004

2. Dressman JB, Comparison of canine and human gastrointestinal physiology, Pharm Res 3(3): pp123-130, 1986

3. Abrahammson B et al, Extrapolation preclinical data to predict human pharmacokinetics: understanding and practice, AAPS Annual Meeting, Los Angeles, California, US, 2009

4. Grass GM and Sinko PJ, Effect of diverse datasets on the predictive capability of ADME models in drug discovery, DDT 6(12) (Suppl) S54-S61, 2001


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John McDermott is the Director of Drug Product Optimisation at Quotient Clinical, a strategic business unit of Quotient Bioresearch specialising in early drug development. After graduating from the University of Hull in 2000, John worked for Rhone Poulenc Rorer and Covance, before joining Quotient Clinical, then Pharmaceutical Profiles, in 2001. After fulfilling roles in the development and validation of radiolabelling methods for solid oral dosage forms, and heading up the pharmaceutical analysis department, John now has overall responsibility for Drug Product Optimisation service, ensuring that the service develops in line with the requirements of the pharmaceutical industry.
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