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This study suggests that a linaclotide dose of 0.5 mg may be appropriate in Japanese patients with IBS-C.

Summary:Two main factors that affect the pharmacokinetics of cyclosporin A (CsA) during 24-h durable intravenous (DIV) administration have been reported, namely physiological changes after bone marrow transplantation, and blood sampling through indwelling lines. In addition, it has been found that infusion sets made of polyvinyl chloride (PVC) markedly adsorb CsA. We conducted in vitro adsorption studies of CsA on infusion sets, and the administration routes that are used in the treatment of patients with bone marrow transplantation. We also examined the effects of administration route on CsA pharmacokinetics in clinical practice. The in vitro adsorption study using 30-mm segments of lumen from commercially available infusion sets showed that the degree of CsA adsorption per area of lumen made of PVC was significantly higher than that in those made of polyethylene (PE) or polybutadiene (PB), which showed no adsorption of CsA. Due to its adsorption, use of infusion sets made of PVC resulted in about a 40-50% loss of CsA dose, which affected the pharmacokinetic parameters during 24-h DIV, while those made of PE and PB did not. The use of non-PVC infusion sets should allow for accurate monitoring of CsA results, and provide cost benefit in the treatment of bone marrow transplantation. Bone Marrow Transplantation (2000) 25, 633-638.

We would like to express sincere gratitude to the interesting comments on our paper 1 by Shearer et al. 2 It is difficult to compare both results directly because different endpoints, different patients' population, different eligible criteria, different drugs prescribed during treatment period, different criteria of adverse events, and different doses of linaclotide are present between 2 studies. However, comparison of results between 0.25 mg of linaclotide (tablet) in our study 1 and 0.29 mg of linaclotide (capsule) in their study 2 would be relatively feasible. Comparable endpoints between 2 studies are only spontaneous bowel movement (SBM), straining, and adverse events.SBM showed 3.8 (mean) at baseline vs 8.9 at 4 weeks in their study 2 and 2.71 (mean) ± 1.13 (SD) at baseline vs 5.86 ± 4.44 at 4 weeks in our study. 1 Straining scored 3.9 at baseline vs 2.0 at 4 weeks in their study 2 and 3.51 (mean) ± 0.74 (SD) at baseline vs 2.62 ± 0.97 at 4 weeks in our study. 1 Note that straining was assessed on 5-point ordinate scale (1, not at all; 2, a little bit; 3, a moderate amount; 4, a great deal; and 5, an extreme amount) in our study. 1 There was no description how they evaluate the straining. 2 In their study at 4 weeks, 56.5% patients continued linaclotide and 43.5% discontinued, 22.2% due to either lack of efficacy or being lost to follow-up, and 21.3% due to adverse events. 2 Overall adverse event rate was 39.8% including 25.9% diarrhea. 2 In our study at 12 weeks, 88.4% patients continued linaclotide and 11.6% discontinued. 1 Despite longer trial period, overall adverse event rate was 41.1% including 17.9% diarrhea. 1Overall adverse event rates were roughly comparable between 2 studies. These findings are consistent with the earlier studies. 3,4 The most impressive difference between our study and their study is discontinuation rate of linaclotide. We can understand that randomized controlled trial is more ideal clinical situation than daily practice. However, from the viewpoint of good clinical practice, basic attitude of biospychosocial model including good physicianpatient relationship which is highly recommended in Japanese IBS guideline 5 may be one of factors of low drop rate. This phenomenon was discussed in the multicultural chapter in Rome IV. 6 Future studies should also clarify potential biological factors including genealogy, gut microbiota, diet, and concomitant therapy (including the ongoing use of laxatives or other constipation-related treatments) which may affect efficacy and safety of linaclotide among different individuals. CO N FLI C T O F I NTE R E S T

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