By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved cholic acid in oral capsule form to treat two rare bile acid synthesis disorders. Patients with these inborn errors of metabolism lack the enzymes to synthesize cholic acid. As a result, the buildup of toxic bile acid intermediaries leads to manifestations of liver disease (cholestasis, giant cell hepatitis, and cirrhosis).1
INDICATIONS
Cholic acid is indicated for the treatment of bile acid synthesis disorders due to single enzyme defects (SED), and as adjunctive treatment of peroxisomal disorder (PD), including Zellweger spectrum disorder in patients who exhibit manifestation of liver disease, steatorrhea, or complications from decreased fat-soluble vitamin absorption.2
DOSAGE
The recommended dose is 10 to 15 mg/kg once daily or in two split doses.2 In patients with concomitant familial hypertriglyceridemia, the dose is 11 to 17 mg/kg once daily or in two split doses and is adjusted based on clinical response. Liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, international normalized ratio, etc.) should be monitored monthly for the first 3 months and every 3 months for the next 9 months, every 6 months for the next 3 years, then annually thereafter. If liver function does not improve after 3 months of treatment or if there is evidence (laboratory or clinical) of worsening liver function, treatment should be discontinued. Cholic acid capsules are available as 50 mg and 250 mg capsules.
POTENTIAL ADVANTAGES
The cholic acid capsule is the first FDA-approved treatment for these rare bile acid synthesis disorders.1
POTENTIAL DISADVANTAGES
The safety and effectiveness of cholic acid on extrahepatic manifestations of bile acid synthesis have not been established.2 Cholic acid may cause decreased liver function in those without baseline liver impairment or exacerbation of liver impairment in those with.2
COMMENTS
The principle of exogenous cholic acid administration for these metabolic disorders is to establish an adequate pool of bile acids to improve micellar solubilization of fats and fat-soluble vitamins, stimulation of bile flow, and inhibition of cholesterol 7alpha-hydroxylase, reducing the production of toxic metabolites from cholesterol.3 The clinical evidence supporting FDA approval involved a non-randomized, single-arm, open-label trial of 50 subjects with SED and 29 with PD.2 In addition, there was an extension trial of 12 new subjects (10 SED and 2 PD) and 31 rolled over from the first study, and lastly 18 patients from case reports or case series (15 SED and 3 PD). Due to the nature of the disease and the lack of a placebo group, a post-hoc method was used to assess efficacy relative to baseline.3 These include 1) improvement in laboratory criteria (e.g., ALT, AST, total bilirubin, normalization of prothrombin time, no evidence of cholestasis) and 2) weight increased or stable at > 50th percentile and alive at the last follow-up. The average treatment duration was 310 weeks for SED and 254 weeks for PD. Sufficient data to evaluate treatment effect were available from 44 SED subjects and 24 PD subjects. Responders were defined as having at least two of the laboratory criteria and were alive at the last follow-up, or at least one laboratory criteria, as well as body weight and survive for at least 3 years on treatment. The rates of response were 64% for SED and 46% for PD. The majority of SED subjects (84%) had a deficiency of 3beta-hydroxysteroid dehydrogenase. The drug was well tolerated, with diarrhea being the most commonly reported adverse event (3%).
CLINICAL IMPLICATIONS
The cholic acid capsule is the first approved treatment of SED and PD. The FDA is recommending a prospective, long-term observational study in a routine clinical setting of patients aged 3 weeks or older with SED or PD who exhibit manifestation of liver disease, steatorrhea, fat soluble vitamin deficiency, or a neuropathic process related to vitamin deficiency.3 At a body weight of 20-30 kg and a dose of 15 mg/kg/day, the 90-day wholesale cost is $74,700.
REFERENCES
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http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm438572.htm. Accessed May 1, 2015.
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Cholbam Prescribing Information. Asklepion Pharmaceuticals LLC. March 2015.
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http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205750Orig1s000TOC.cfm. Accessed May 6, 2015.
