The Provisional No-Effect Threshold of Sugar Alcohols on Oral Drug Absorption Estimated by Physiologically Based Biopharmaceutics Model.

Sugar alcohols reduce oral drug bioavailability by osmotic effects, but the magnitude of these effects differs among different drugs. This study aimed to identify the drug-related critical attributes of osmotic effects and estimate the impact of a "practical" sugar alcohol dose on the pharmacokinetics of various molecules using modeling and simulation approaches. We developed a physiologically based biopharmaceutics model that considers the dose-dependent effects of sugar alcohols on the gastrointestinal physiology. The developed model captured the effects of sugar alcohols on ranitidine hydrochloride, metoprolol tartrate, theophylline, cimetidine, and lamivudine. Sensitivity analysis provided quantitative insights into the effects of sugar alcohols dependent on different drug permeability. In addition, our developed model indicated for the first time that a high systemic elimination rate is crucial for the reduction in maximum plasma concentration even for highly permeable drugs. Nonetheless, mannitol/sorbitol level of less than 400 mg had minor effects on the pharmacokinetics of the most sensitive drugs, indicating a provisional no-effect threshold dose. This mechanistic approach provides comprehensive estimation of osmotic effects on variety of drugs. Subsequently, these findings may invoke scientific discussion on the criteria for excipient changes in the context of biowaiver guidelines (e.g. biopharmaceutics classification system-based biowaiver).

In vivo analysis of supersaturation/precipitation/absorption behavior after oral administration of pioglitazone hydrochloride salt; determinant site of oral absorption.

The purpose of this study was to evaluate in vivo supersaturation/precipitation/absorption behavior in the gastrointestinal (GI) tract based on the luminal concentration-time profiles after oral administration of pioglitazone (PG, a highly permeable lipophilic base) and its hydrochloride salt (PG-HCl) to rats. In the in vitro precipitation experiment in the classic closed system, while the supersaturation was stable in the simulated gastric condition, PG drastically precipitated in the simulated intestinal condition, particularly at a higher initial degree of supersaturation. Nonetheless, a drastic and moderate improvement in absorption was observed in vivo at a low and high dose of PG-HCl, respectively. Analysis based on the luminal concentration of PG after oral administration of PG-HCl at a low dose revealed that most of the dissolved PG emptied from the stomach was rapidly absorbed before its precipitation in the duodenum. At a high dose of PG-HCl, PG partly precipitated in the duodenum but was absorbed to some extent. Therefore, the extent of the absorption was mainly dependent on the duodenal precipitation behavior. Furthermore, a higher-than expected absorption after oral administration of PG-HCl from in vitro precipitation study may be due to the absorption process in the small intestine, which suppresses the precipitation by removal of the drug. This study successfully clarify the impact of the absorption process on the supersaturation/precipitation/absorption behavior and key absorption site for a salt formulation of a highly permeable lipophilic base based on the direct observation of in vivo luminal concentration. Our findings may be beneficial in developing an ideal physiologically based pharmacokinetic model and in vitro predictive dissolution tools and/or translating the in silico and in vitro data to the in vivo outcome.

CYP3A activity based on plasma 4ß-hydroxycholesterol during the early postpartum period has an effect on the plasma disposition of amlodipine.

This study aimed to evaluate plasma 4ß-hydroxycholesterol as an endogenous marker of CYP3A4/5 activity in early postpartum women and its impact on the plasma disposition of amlodipine. Twenty-seven early postpartum women treated with amlodipine for pregnancy-induced hypertension were enrolled. The plasma concentration of 4ß-hydroxycholesterol and its ratio to cholesterol in postpartum and in non-perinatal women were evaluated. The predose plasma concentration of amlodipine was determined at steady state. The medians of the plasma 4ß-hydroxycholesterol concentration at day 0-3 and 8-21 after delivery were 146 and 161 ng/mL, respectively. No significant difference was observed in the plasma concentration of 4ß-hydroxycholesterol between the postpartum periods. The plasma concentration of 4ß-hydroxycholesterol and its ratio to cholesterol in postpartum women were significantly higher than those in non-perinatal women. A large individual variability was observed in the dose-normalized plasma concentration of amlodipine in early postpartum women. A weak negative correlation was observed between the dose-normalized plasma concentration of amlodipine and the plasma concentration of 4ß-hydroxycholesterol. In conclusion, early postpartum women possessed higher CYP3A activity based on plasma 4ß-hydroxycholesterol and had a large pharmacokinetic variability in amlodipine. CYP3A activity during the early postpartum period had an effect on the plasma disposition of amlodipine.

Analysis of Intra- and Intersubject Variability in Oral Drug Absorption in Human Bioequivalence Studies of 113 Generic Products.

In this study, the data of 113 human bioequivalence (BE) studies of immediate release (IR) formulations of 74 active pharmaceutical ingredients (APIs) conducted at Sawai Pharmaceutical Co., Ltd., was analyzed to understand the factors affecting intra- and intersubject variabilities in oral drug absorption. The ANOVA CV (%) calculated from area under the time-concentration curve (AUC) in each BE study was used as an index of intrasubject variability (Vintra), and the relative standard deviation (%) in AUC was used as that of intersubject variability (Vinter). Although no significant correlation was observed between Vintra and Vinter of all drugs, Vintra of class 3 drugs was found to increase in association with a decrease in drug permeability (P(eff)). Since the absorption of class 3 drugs was rate-limited by the permeability, it was suggested that, for such drugs, the low P(eff) might be a risk factor to cause a large intrasubject variability. To consider the impact of poor water solubility on the variability in BE study, a parameter of P(eff)/Do (Do; dose number) was defined to discriminate the solubility-limited and dissolution-rate-limited absorption of class 2 drugs. It was found that the class 2 drugs with a solubility-limited absorption (P(eff)/Do < 0.149 × 10(-4) cm/s) showed high intrasubject variability. Furthermore, as a reason for high intra- or intersubject variability in AUC for class 1 drugs, effects of drug metabolizing enzymes were investigated. It was demonstrated that intrasubject variability was high for drugs metabolized by CYP3A4 while intersubject variability was high for drugs metabolized by CYP2D6. For CYP3A4 substrate drugs, the Km value showed the significant relation with Vintra, indicating that the affinity to the enzyme can be a parameter to predict the risk of high intrasubject variability. In conclusion, by analyzing the in house data of human BE study, low permeability, solubility-limited absorption, and high affinity to CYP3A4 are identified as risk factors for high intrasubject variability in oral drug absorption. This information is of importance to design the human BE study for oral drug products containing APIs with a risk of large intrasubject variability in oral absorption.

Amlodipine passage into breast milk in lactating women with pregnancy-induced hypertension and its estimation of infant risk for breastfeeding.

BACKGROUND: Few clinical reports have been published on amlodipine passage into breast milk in lactating women. OBJECTIVES: The aims of this study were to evaluate the plasma concentration of amlodipine and its passage into breast milk in lactating women with pregnancy-induced hypertension and to estimate the risk for breastfeeding infants. METHODS: Thirty-one lactating women receiving oral amlodipine once daily for pregnancy-induced hypertension were enrolled. Pre-dose plasma and milk concentrations of amlodipine were determined at day 6 or later after starting the medication. Relative infant dose (RID) as an infant risk for breastfeeding was calculated by dividing the infant dose via milk by the maternal dose. RESULTS: The mean maternal dose of amlodipine was 6.0 mg. The medians of the plasma and milk concentrations of amlodipine were 15.5 and 11.5 ng/mL, respectively. Interindividual variation was observed in the amlodipine dose and body weight-adjusted milk concentrations (interquartile range [IQR], 96.7-205 ng/mL per mg/kg). The median and IQR of the amlodipine concentration ratio of milk to plasma were 0.85 and 0.74 to 1.08, respectively. The medians of infant birth weight and daily amlodipine dose via milk were 2170 g and 4.2 µg/kg, respectively. The median of the RID of amlodipine was 4.2% (IQR, 3.1%-7.3%). CONCLUSION: Lactating women with pregnancy-induced hypertension had higher plasma concentrations of amlodipine during the early postpartum period. Oral amlodipine transferred into breast milk at the same level as that of plasma. However, the RID of amlodipine in most patients was less than 10%.

Effect of excipients on the particle size of precipitated pioglitazone in the gastrointestinal tract: impact on bioequivalence.

This study sought to understand the reasons for the bioinequivalence of a newly developed generic product of pioglitazone hydrochloride and to improve its formulation so that it is equivalent to that of the reference listed drug (RLD). In this clinical study, despite a similar in vitro dissolution profile, the new oral product exhibited a lower plasma concentration of pioglitazone compared to the RLD. The strong pH-dependency of pioglitazone solubility as a weak base indicates that pioglitazone would precipitate in the small intestine after being dissolved in the stomach. Thus, in vitro experiments were performed to investigate the effect of excipients on the particle size distribution of precipitated pioglitazone. Then, the impact of particle size on in vivo absorption was discussed. The precipitated pioglitazone from the RLD showed a peak for small particles (less than 1 µm), which was not observed in the precipitate from the new product. As an excipient, hydroxypropyl cellulose (HPC) influenced the particle size of precipitated pioglitazone, and the amount of HPC in the formulation was increased to the same level as that in the RLD. The precipitate from this improved product showed approximately the same particle size distribution as that of the RLD and successfully demonstrated bioequivalence in the clinical study. In conclusion, for drugs with low solubility, this type of analysis of the particle size distribution of precipitated drugs, in addition to the dissolution test, may help to obtain a better in vitro-in vivo correlation for oral absorption and to develop a bioequivalent product.