Kiyomi Ito

Creatinine is a common biomarker of renal function and is secreted in the renal tubular cells via drug transporters such as organic cation transporter 2 and multidrug and toxin extrusion (MATE) 1/2-K. To differentiate between drug-induced acute kidney injury (AKI) and drug interactions through the renal transporter, it has been examined whether these transporter inhibitions quantitatively explained increases in serum creatinine (SCr) at their clinically relevant concentrations using drugs without any changes in renal function. For such renal transporter inhibitors and recently approved tyrosine kinase inhibitors (TKIs), this mini-review describes clinical increases in SCr and inhibitory potentials against the renal transporters. Most cases of SCr elevations can be explained by considering the renal transporter inhibitions based on unbound maximum plasma concentrations, except for drugs associated with obvious changes in renal function. SCr increases for cobicistat, dolutegravir, and dronedarone, and some TKIs were significantly underestimated, and these underestimations were suggested to be associated with low plasma unbound fractions. Sensitivity analysis of SCr elevations regarding inhibitory potentials of MATE1/2-K demonstrated that typical inhibitors such as cimetidine, DX-619, pyrimethamine, and trimethoprim could give false interpretations of AKI according to the criteria based on relative or absolute levels of SCr elevations. Recent progress and current challenges of physiologically-based pharmacokinetics modeling for creatinine disposition were also summarized. Although it should be noted for the potential impact of in vitro assay designs on clinical translatability of transporter inhibitions data, mechanistic approaches could support decision-making in clinical development to differentiate between AKI and creatinine-drug interactions. Significance Statement Serum creatinine (SCr) is widely used as an indicator of kidney function, but it increases due to inhibitions of renal transporters such as multidrug and toxin extrusion protein ½-K despite no functional changes in the kidney. Such SCr elevations were quantitatively explained by renal transporter inhibitions except for some drugs with high protein binding. The present analysis demonstrated that clinically relevant inhibitors of the renal transporters could cause SCr elevations above levels corresponding to acute kidney injury criteria.

BACKGROUND: Caffeine consumption is a risk factor for chronic daily headache but few studies have addressed relationships between pediatric patient caffeine levels and headache severity. We examined associations between serum and urine caffeine levels and headache severity in childhood and adolescent migraine cases. METHODS: Levels of caffeine and caffeine metabolites in serum and urine samples were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The Wilcoxon rank-sum test was used for comparisons of age, sleep time, headache severity, caffeine consumption, and caffeine detection. Spearman's rank correlation coefficient (ρ) was calculated for associations. Correlations where ρ ≥ 0.3 and differences where p < 0.05 were considered statistically significant. RESULTS: Of the 40 patients studied, 34 declared caffeine consumption and six declared no caffeine consumption. These two groups did not differ significantly in any of the above clinical parameters. Liquid chromatography-tandem mass spectrometry analysis of both serum and urine samples revealed nine caffeine-negative (level <0.0625 μM) and 31 caffeine-positive cases. The Headache Impact Test-6 (HIT-6) score was higher (p = 0.033) for the caffeine-positive group versus the caffeine-negative group. Caffeine was detected by LC-MS/MS in the serum and/or urine of three of the six patients who declared no caffeine consumption. No significant correlations were observed among age, sleep times, headache severity score, or levels of caffeine and caffeine metabolites. CONCLUSION: Thirty one of 40 (77.5%) cases of childhood/ adolescence migraine showed serum and urine caffeine positivity based on LC-MS/MS. The HIT-6 score, a measure of headache severity, was significantly higher for caffeine-positive versus caffeine-negative cases. Symptoms of childhood/adolescence migraine were exacerbated by caffeine consumption.

During new drug development, clinical drug interaction studies are carried out in accordance with the mechanism of potential drug interactions evaluated by in vitro studies. The obtained information should be provided efficiently to medical experts through package inserts and various information materials after the drug's launch. A recently updated Japanese guideline presents general procedures that are considered scientifically valid at the present moment. In this review, we aim to highlight the viewpoints of the Japanese guideline and enumerate drugs that were involved or are anticipated to be involved in evident pharmacokinetic drug interactions and classify them by their clearance pathway and potential intensity based on systematic reviews of the literature. The classification would be informative for designing clinical studies during the development stage, and the appropriate management of drug interactions in clinical practice.

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor, used for the treatment of human immunodeficiency virus type-1 infection. An open label study was conducted to investigate the pharmacokinetics (PK) and safety of a single oral dose of rilpivirine 25 mg in Japanese healthy adult subjects. No adverse events were reported. The mean Cmax (144.3 ng/mL) and AUCinf (4542 ng h/mL) in Japanese subjects were approximately 30 % higher than those reported from a similar study in Caucasian healthy subjects, whereas the median tmax and mean t1/2 values were comparable between studies. A simple physiologically based PK model was developed to characterize the rilpivirine PK profile. The model adequately described rilpivirine PK profiles, and well-predicted drug-drug interactions. With exploration using the model, body size and CYP3A4 abundance were identified as factors which explained the observed inter-ethnic difference in rilpivirine exposure. The inter-ethnic difference in rilpivirine exposure was however considered not clinically relevant, since inter-individual variabilities of those intrinsic factors are larger than inter-ethnic ones; and the observed AUCinf in Japanese subjects was within the range of AUCtau associated with efficacy and safety in Phase 3 studies. This study results support the use of rilpivirine without dose modification specific to Japanese patients.