Praziquantel (PZQ), the primary drug of choice in the treatment of schistosomiasis, is a highly lipophilic drug that possesses high permeability and low aqueous solubility and is, therefore, classified as a Class II drug according to the Biopharmaceutics Classification System (BCS). In this work, beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were used in order to determine whether increasing the aqueous solubility of a drug by complexation with CDs, a BCS-Class II compound like PZQ could behave as BCS-Class I (highly soluble/highly permeable) drug. Phase solubility and the kneading and lyophilization techniques were used for inclusion complex preparation; solubility was determined by UV spectroscopy. The ability of the water soluble polymer polyvinylpyrolidone (PVP) to increase the complexation and solubilization efficiency of beta-CD and HP-beta-CD for PZQ was examined. Results showed significant improvement of PZQ solubility in the presence of both cyclodextrins but no additional effect in the presence of PVP. The solubility/dose ratios values of PZQ-cyclodextrin complexes calculated considering the low (150 mg) and the high dose (600 mg) of PZQ, used in practice, indicate that PZQ complexation with CDs may result in drug dosage forms that would behave as a BCS-Class I depending on the administered dose.

Therapeutic proteins are a diverse class of drugs consisting of naturally occurring or modified proteins, and due to their size and physico-chemical properties, they can pose challenges for the pharmacokinetic and pharmacodynamic studies. Physiologically-based pharmacokinetics (PBPK) modelling has been effective for early in silico prediction of pharmacokinetic properties of new drugs. The aim of the present workshop was to discuss the feasibility of PBPK modelling of macromolecules. The classical PBPK approach was discussed with a presentation of the successful example of PBPK modelling of cyclosporine A. PBPK model was performed with transport of the cyclosporine across cell membranes, affinity to plasma proteins and active membrane transporters included to describe drug transport between physiological compartments. For macromolecules, complex PBPK modelling or permeability-limited and/or target-mediated distribution was discussed. It was generally agreed that PBPK modelling was feasible and desirable. The role of the lymphatic system should be considered when absorption after extravascular administration is modelled. Target-mediated drug disposition was regarded as an important feature for generation of PK models. Complex PK-models may not be necessary when a limited number of organs are affected. More mechanistic PK/PD models will be relevant when adverse events/toxicity are included in the PK/PD modelling.

To compare the performance of the reference scaled average bioequivalence(scABE(R)) method proposed by FDA scientists {[}Haidar et al., 2008. Pharm. Res. 25,237-241] with other approaches focusing on the human exposure expressed as the product sample size x periods of drug administration. Simulated bioequivalence studies were generated assuming the partial replicate 3-way crossover design and the classic (2 x 2) crossover design. Intrasubject variability (CV(W)) values ranged from 15% to 60% and sample sizes from 16 to 54. The procedures examined include: the scABER method. the classic 0.80-1.25 approach, a levelling-off scaled BE limit (BELscW), and some other scaled bioequivalence lit-nits. To assess the performance of the aforementioned approaches, the typical as well as novel three-dimensional modified power curves were constructed. A new index, termed %Mean Relative Difference (MRD%). was introduced in order to quantitatively compare the performance of the bioequivalence limits. The recently proposed scABER approach showed the lowest producer risk in particular for highly variable drugs. When exposure was taken into account scABER resulted in a desired behaviour when CV(W) was low. For high CV(W) values the overall performance diminished when geometric mean ratio (GMR) substantially deviated from unity. Application of the MRD% index clearly revealed that the effect of lowering the producer risk at GMR = I was totally Counterbalanced by the rise of consumer risk at high GMR values. The classic 0.80-1.25 limits were favoured at low intrasubject variability and high exposure, whereas the levelling-off limits demonstrated a preferred overall performance when variability was high and exposure was limited. (C) 2009 Elsevier B.V. All rights reserved.

We explore the use of fractional order differential equations for the analysis of datasets of various drug processes that present anomalous kinetics, i.e. kinetics that are non-exponential and are typically described by power-laws. A fractional differential equation corresponds to a differential equation with a derivative of fractional order. The fractional equivalents of the ``zero-{''} and ``first-order{''} processes are derived. The fractional zero-order process is a power-law while the fractional first-order process is a Mittag-Leffler function. The latter behaves as a stretched exponential for early times and as a power-law for later times. Applications of these two basic results for drug dissolution/release and drug disposition are presented. The fractional model of dissolution is fitted successfully to datasets taken from literature of in vivo dissolution curves. Also, the proposed pharmacokinetic model is fitted to a dataset which exhibits power-law terminal phase. The Mittag-Leffler function describes well the data for small and large time scales and presents an advantage over empirical power-laws which go to infinity as time approaches zero. The proposed approach is compared conceptually with fractal kinetics, an alternative approach to describe datasets with non exponential kinetics. Fractional kinetics offers an elegant description of anomalous kinetics, with a valid scientific basis, since it has already been applied in problems of diffusion in other fields, and describes well the data.