Australian public assessment for Ibuprofen - Therapeutic Goods ...

III. Nonclinical findings
Introduction
General comments
AusPAR Caldolor Ibuprofen Phebra Pty Ltd PM-2010-02393-3-1
Final 2 January 2013
Therapeutic Goods Administration
The toxicity profile of ibuprofen has been previously characterised and there is extensive
clinical experience with its use. In order to justify the new route of administration, the
sponsor submitted bridging studies, which included two 28 day IV toxicity studies (with
toxicokinetic data), blood compatibility studies and local irritation studies. The general
quality of the submitted studies was good. Pivotal studies examining the repeat-dose
toxicity were conducted under Good laboratory Practice (GLP) conditions. Additional
submitted studies included dose range-finding IV studies and published repeat dose
toxicity studies in rats (oral (PO)), dogs (PO) and monkeys (IV/PO), single dose toxicity
studies, genotoxicity studies and reproductive toxicity studies.
The proposed maximum recommended human dose (MRHD) is 3200 mg/day, therefore a
50 kg patient receiving the MRHD would receive 64 mg/kg ibuprofen. The MRHD for
ibuprofen administered orally is 2400 mg/day.
Studies in the submitted published literature which were not performed with IV ibuprofen,
or with the proposed formulation, were not assessed.
Pharmacology
Mechanism of action
Like that of other NSAIDs, ibuprofen’s mechanism of action is not completely understood
but may be related to inhibition of cyclooxygenase mediated prostaglandin formation.
Ibuprofen possesses anti-inflammatory, analgesic, and antipyretic activity. Ibuprofen
inhibits both COX-1 and COX-2 activities and thereby synthesis of prostaglandins and
thromboxanes. The inhibition of COX-1 is believed to be responsible for the
gastrointestinal (GI) adverse effects related to ibuprofen administration 1.
No pharmacodynamics studies were submitted and this was considered acceptable as
there is extensive clinical efficacy data from clinical experience with ibuprofen.
Pharmacokinetics
In the submitted dog studies, oral administration of ibuprofen resulted in lower plasma
drug concentration and overall exposure (50-60%) when compared with IV
administration at the same dose level. In the two clinical studies in which equal IV and PO
doses were compared (Table 1), plasma area under the plasma concentration time curve
(AUC) values were similar, indicating 100% PO bioavailability under the conditions of
these studies.
In general, all measured parameters were similar between genders and sampling days.
AUC and peak plasma concentration (Cmax) values were dose proportional for both males
and females on both sampling days and no clear sex differences in systemic exposure were
1 Insel PA. Analgesic-antipyretic and anti-inflammatory agents and drugs employed in the treatment of
gout. Chapter 27. In: Hardman J. G. and Limbird L. E. The Pharmacological Basis of Therapeutic. Mc Graw
Hill, 1990: 617-658
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