Lost in modelling and simulation?

Over the past few decades, physiologically-based pharmacokinetic modelling (PBPK) has been anticipated to be a powerful tool to improve the productivity of drug discovery and development. However, recently, multiple systematic evaluation studies independently suggested that the predictive power of current oral absorption (OA) PBPK models needs significant improvement. There is some disagreement between the industry and regulators about the credibility of OA PBPK modelling. Recently, the editorial board of AMDET&DMPK has announced the policy for the articles related to PBPK modelling (Modelling and simulation ethics). In this feature article, the background of this policy is explained: (1) Requirements for scientific writing of PBPK modelling, (2) Scientific literacy for PBPK modelling, and (3) Middle-out approaches. PBPK models are a useful tool if used correctly. This article will hopefully help advance the science of OA PBPK models.

Permeation characteristics of tetracyclines in parallel artificial membrane permeation assay

The purpose of the present study was to characterize the passive permeation of tetracyclines in the parallel artificial membrane permeation assay (PAMPA). Tetracyclines exist as zwitterion at physiological pH. The PAMPA membrane was prepared by impregnating a phospholipid/decane solution to a filter support. The permeation coefficient (Pe) of tetracycline (TC) was markedly affected by the lipid composition of the PAMPA membrane. No permeation was observed when phospholipid was not added (pure decane membrane, Pe < 0.05 × 10-6 cm/sec). With the addition of 2 % PC, little or no increase in Pe was observed. The addition of 1 % PE increased the Pe value more than tenfold. The addition of 2 % soybean lecithin containing phosphatidylinositol (PI) and phosphatidic acid (PA) increased the Pe value to above 4 × 10-6 cm/sec. The Pe value was further increased to 15 × 10-6 cm/sec by increasing the concentration of soybean lecithin from 2 to 10 %. The Pe value showed pH and temperature dependence, whereas it was not affected by the ionic strength, TC concentration, and ion-pair transport inhibitors. A weak correlation was observed between the Pe values and octanol-buffer distribution coefficients of tetracyclines. These results suggest that inter-molecular interactions between TC and PE, PI and/or PA facilitate the passive diffusion of TC across the PAMPA membrane

Food and bile micelle binding of quaternary ammonium compounds

Background and Purpose Physiologically-based biopharmaceutics modeling (PBBM) has been widely used to predict the oral absorption of drugs. However, the prediction of food effects on oral drug absorption is still challenging, especially for negative food effects. Marked negative food effects have been reported in most cases of quaternary ammonium compounds (QAC). However, the mechanism has remained unclear. The purpose of the present study was to investigate the bile micelle and food binding of QACs as a mechanism of the negative food effect. Experimental Approach Trospium (TRS), propantheline (PPT), and ambenonium (AMB) were selected as model QAC drugs. The oral absorption of these QACs has been reported to be reduced by 77% (TRS), > 66% (PPT), and 79% (AMB), when taken with food. The fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF, containing 3 and 15 mM taurocholic acid, respectively) with or without FDA breakfast homogenate (BFH) were used as the simulated intestinal fluid. The unbound fraction (fu) of the QACs in these media was measured by dynamic dialysis. Key Results The fu ratios (FeSSIF/ FaSSIF) were 0.67 (TRS), 0.47 (PPT), and 0.76 (AMB). When BFH was added to FeSSIF, it was reduced to 0.39 (TRS), 0.28 (PPT), and 0.59 (AMB). Conclusion These results suggested that bile micelle and food binding play an important role in the negative food effect on the oral absorption of QACs

Reversed phase parallel artificial membrane permeation assay for log P measurement

A reversed phase parallel artificial membrane permeation assay (RP-PAMPA) was newly invented for log P measurement. An oil/water/oil sandwich was constructed using a conventional PAMPA instrument. 1 % agarose was used to improve the physical stability of the water phase. A linear correlation between log P and the apparent permeability was observed in the -0.24 < log P < 2.85 region (R2 = 0.98). RP-PAMPA was also applied to pKa measurement

Permeation characteristics of tetracyclines in parallel artificial membrane permeation assay II: Effect of divalent metal ions and mucin

The bioavailability of tetracyclines is markedly decreased when co-administered with antacids, milk, or food containing Ca2+. Previously, it was suggested that the effective intestinal permeation of tetracycline (TC) was decreased due to Ca2+ linked mucin binding in the mucosal side. In the present study, we investigated the effect of Ca2+, Mg2+, and mucin on the membrane permeation of six tetracyclines (TC, oxytetracycline (OTC), minocycline (MINO), doxycycline (DOXY), demeclocycline (DMCTC), and chlortetracycline (CTC)). The membrane permeability values (Pe) of tetracyclines were measured by the parallel artificial membrane permeation assay (PAMPA) using soybean lecithin – decane (SL–PAMPA) and octanol (OCT–PAMPA) membranes. In SL–PAMPA, Ca2+ markedly decreased the Pe values of all tetracyclines. In OCT–PAMPA, Ca2+ increased the Pe values of TC, CTC, and DMCTC, but not DOXY, OTC, and MINO. Mg2+ decreased the Pe values of all tetracyclines in both SL–PAMPA and OCT–PAMPA (except for CTC in OCT–PAMPA). The addition of mucin had little or no effect in all cases. In contrast to the previously suggested mechanism, the results of the present study suggested that Ca2+ chelate formation decreased the membrane permeation of tetracyclines, irrespective of Ca2+ linked mucin binding. Molecular speciation analysis suggested that the permeation of TC – metal chelates was negligibly small in SL-PAMPA

Harmonizing solubility measurement to lower inter-laboratory variance – progress of consortium of biopharmaceutical tools (CoBiTo) in Japan

The purpose of the present study was to harmonize the protocol of equilibrium solubility measurements for poorly water-soluble drugs to lower inter-laboratory variance. The “mandatory” and “recommended” procedures for the shake-flask method were harmonized based on the knowledge and experiences of each company and information from the literature. The solubility of model drugs was measured by the harmonized protocol (HP) and the non-harmonized proprietary protocol of each company (nonHP). Albendazole, griseofulvin, dipyridamole, and glibenclamide were used as model drugs. When using the nonHP, the solubility values showed large inter-laboratory variance. In contrast, inter-laboratory variance was markedly reduced when using the HP

Effect of divalent and trivalent metal ions on artificial membrane permeation of fluoroquinolones1

The purpose of the present study was to evaluate the predictability of PAMPA for the effect of metal ions on the bioavailability of fluoroquinolones (FQ). Eleven FQs and seven metal ions were employed in this study. The PAMPA membrane consisted of a 10 % soybean lecithin (SL) – decane solution. A drug solution in MES buffer with or without a metal ion (added as a chloride salt) was added to the donor compartment. In the absence of metal ions, FQ showed relatively high permeability (> 5 × 10-6 cm/sec) in SL-PAMPA despite their hydrophilic and zwitterionic properties. As the PAMPA permeability ratio with/without metal ions became smaller, the urinary excretion and AUC ratios tended to be smaller, suggesting that SL-PAMPA is a suitable in vitro model to evaluate the potential effect of metal ions on the bioavailability of FQ. However, the reduction in AUC and urinary excretion was overestimated for low solubility metal ion formulations (dried aluminum hydroxide gel and La2(CO3)3・8H2O). In such cases, the dissolution of the metal ion formulations and the permeation of FQs should be simultaneously evaluated

Thermodynamic Correlation between Liquid&ndash;Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules

The purpose of the present study was to experimentally confirm the thermodynamic correlation between the intrinsic liquid&ndash;liquid phase separation (LLPS) concentration (S0LLPS) and crystalline solubility (S0c) of drug-like molecules. Based on the thermodynamic principles, the crystalline solubility LLPS concentration melting point (Tm) equation (CLME) was derived (log10S0C=log10S0LLPS&minus;0.0095Tm&minus;310 for 310 K). The S0LLPS values of 31 drugs were newly measured by simple bulk phase pH-shift or solvent-shift precipitation tests coupled with laser-assisted visual turbidity detection. To ensure the precipitant was not made crystalline at &lt;10 s, the precipitation tests were also performed under the polarized light microscope. The calculated and observed log10S0C values showed a good correlation (root mean squared error: 0.40 log unit, absolute average error: 0.32 log unit)