Physicochemical properties, pharmacokinetics, and pharmacodynamics of intravenous hematin: a literature review.
BACKGROUND
Intravenous (i.v.) hematin has been used in the treatment of acute intermittent porphyria (AIP) since the early 1970s and commercially available as Panhematin (hemin for injection; Ovation Pharmaceuticals, Inc., USA) since 1983, yet no publication to date has attempted to summarize the known pharmacodynamics and toxicological actions of hematin and the implications on treatment. It is the objective of this literature review to identify, consolidate, and summarize the available scientific literature regarding the physicochemical properties, pharmacokinetics, toxicology, and hemostatic effects of i.v. hematin injections.


METHODS
A comprehensive search of the available literature was performed and resulting data were summarized. Furthermore, previously unpublished toxicology data extracted from the original New Drug Application were included.


RESULTS
Hematin, reconstituted with sterile water, rapidly degrades and it is hypothesized that the degradation products lead to morbidities such as thrombophlebitis, thrombocytopenia, and transient anticoagulation. Reconstitution with human serum albumin produces a well-tolerated hematin preparation and improves its stability significantly. The clearance of i.v. hematin infusions are shown to fit a two-compartment model consisting of a rapid initial rate followed by a slower and prolonged second phase. This model is supported by the evidence demonstrating that hematin is first bound by hemopexin and, upon saturation, second by albumin. The highest i.v. human hematin dose reported in the literature was 12.2 mg/kg (1000 mg) and resulted in acute gastrointestinal pain, paresthesia, and acute tubercular necrosis. The patient's renal function returned to normal over the following 15 hours.


CONCLUSIONS
Hematin, at doses approved by the US Food and Drug Administration, is generally well tolerated. Reconstitution with albumin produces a significantly more stable preparation than reconstitution with sterile water and may lead to a more tolerable administration with less hemostatic interference. Hematin, once administered, is cleared hepatically and is best represented pharmacokinetically by a two-compartment model comprised of a rapid initial phase followed by a slower second phase.
Siegert
Scott W K
SW
University of Illinois at Chicago College of Pharmacy, Illinois, USA. ssiegert@ovationpharma.com
Holt
Robert J
RJ
D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006401:Hematologic Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D006427:Hemin / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D017118:Porphyria, Acute Intermittent / Q000188:drug therapy; D012709:Serum Albumin / Q000737:chemistry
D006401:Hematologic Agents; D012709:Serum Albumin; D006427:Hemin