Cyclosporine-Induced Pseudoporphyria

Hivnor, Chad; Nosauri, Carlos; James, William D.; Poh–Fitzpatrick, Maureen B.

doi:10.1001/archderm.139.10.1373

Cited by 17 publications

(7 citation statements)

References 4 publications

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“…In line with the increase in RSV exposure, as seen in Tables 1 and 2, CsA increased CPs I and III plasma exposures by 2.7-and 5.2-fold, and RIF increased those by 2.7-and 3.6-fold, respectively. These observations agree with clinical findings that CsA and RIF caused drug-induced porphyria, which refers to increased levels of circulating porphyrins including CP in patients (Millar, 1980;Hivnor et al, 2003), likely due to the inhibition of OATP1B1 and OATP1B3. Urinary excretion of CP I was increased to a similar extent compared with the changes in CP I AUC (3.5-versus 2.7-fold and 2.7-versus 4.3-fold by CsA and RIF, respectively).…”

Section: Discussionsupporting

confidence: 91%

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Shen

Dai

Liu

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

109

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Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions, thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity. Active uptake of CPs I and III was observed in human embryonic kidney (HEK) 293 cells singly expressing human OATP1B1 (hOATP1B1), hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or cOATP1B3, as well as human and monkey hepatocytes. Cyclosporin A (100 mg/kg, oral) markedly increased the area under the curve (AUC) plasma concentrations of CPs I and III by 2.6-and 5.2-fold, while rifampicin (15 mg/kg, oral) increased the AUCs by 2.7-and 3.6-fold, respectively. As the systemic exposure increased, the excretion of both isomers in urine rose from 1.6-to 4.3-fold in monkeys. In agreement with this finding, the AUC of rosuvastatin (RSV) in cynomolgus monkeys increased when OATP1B inhibitors were coadministered. In Oatp1a/1b gene cluster knockout mice (Oatp1a/1b 2/2 ), CPs in plasma and urine were significantly increased compared with wild-type animals (7.1-to 18.4-fold; P , 0.001), which were also in agreement with the changes in plasma RSV exposure (14.6-fold increase). We conclude that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function, and the measurements have the potential to be incorporated into the design of early clinical evaluation.

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Section: Discussionsupporting

confidence: 91%

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Shen

Dai

Liu

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

109

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“…Indeed, the plasma concentrations of both CP-I and CP-III in cynomolgus monkeys were markedly increased following administration of OATP inhibitors cyclosporine A (100 mg/kg oral) or RIF (15 mg/kg oral) (Shen et al, 2015(Shen et al, , 2016b. The observations in monkey could explain the clinical findings that cyclosporine A-or RIF-induced porphyria in patients is likely due to the inhibition of OATP transporters (Millar, 1980;Hivnor et al, 2003). In addition, changes in plasma CP-I and CP-III in cynomolgus monkey are in line with RSV exposure increase after coadministration with OATP inhibitors, suggesting CPs could be biomarkers for in vivo OATP-mediated DDIs (Shen et al, 2016a).…”

Section: Discussionmentioning

confidence: 94%

Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition

Lai

Mandlekar

Shen

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

145

203

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In the present study, an open-label, three-treatment, threeperiod clinical study of rosuvastatin (RSV) and rifampicin (RIF) when administered alone and in combination was conducted in 12 male healthy subjects to determine if coproporphyrin I (CP-I) and coproporphyrin III (CP-III) could serve as clinical biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 that belong to the solute carrier organic anion gene subfamily. Genotyping of the human OATP1B1 gene was performed in all 12 subjects and confirmed absence of OATP1B1*5 and OATP1B1*15 mutations. Average plasma concentrations of CP-I and CP-III prior to drug administration were 0.91 6 0.21 and 0.15 6 0.04 nM, respectively, with minimum fluctuation over the three periods. CP-I was passively eliminated, whereas CP-III was actively secreted from urine. Administration of RSV caused no significant changes in the plasma and urinary profiles of CP-I and CP-III. RIF markedly increased the maximum plasma concentration (C max ) of CP-I and CP-III by 5.7-and 5.4-fold (RIF) or 5.7-and 6.5-fold (RIF1RSV), respectively, as compared with the predose values. The area under the plasma concentration curves from time 0 to 24 h (AUC 0-24h ) of CP-I and CP-III with RIF and RSV increased by 4.0-and 3.3-fold, respectively, when compared with RSV alone. In agreement with this finding, C max and AUC 0-24h of RSV increased by 13.2-and 5.0-fold, respectively, when RIF was coadministered. Collectively, we conclude that CP-I and CP-III in plasma and urine can be appropriate endogenous biomarkers specifically and reliably reflecting OATP inhibition, and thus the measurement of these molecules can serve as a useful tool to assess OATP drug-drug interaction liabilities in early clinical studies.

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“…1 Complete responders account for 16% 2 to 26% 3 and partial responses vary between 35% 4 and 53%. 3,5,6 Nevertheless, these survival increases should be confirmed by controlled studies. 3,5,6 Nevertheless, these survival increases should be confirmed by controlled studies.…”

Section: Photopheresis Does Not Improve Survival In Sézary Syndrome Pmentioning

confidence: 96%

“…Many drugs have been implicated as triggering factors, such as nonsteroidal anti-inflammatory drugs (especially naproxen), furosemide, thyazides, tetracyclines, the recently described rofecoxib 1 and celecoxib, 2 cyclosporine, 3 and oral contraceptive pills. Clinically and histologically it resembles porphyria cutanea tarda, but quantitative porphyrines studies are within normal limits.…”

Section: Pseudoporhyria Secondary To Acitretinmentioning

confidence: 99%