Clinical Pharmacokinetics of Drugs Used in Juvenile Arthritis

Abstract

Juvenile arthritis is defined as the occurrence of objective evidence of arthritis for a minimum of 6 weeks, in a child 16 years of age or younger. With a reported incidence of 9 to 19.6 per 100,000 children, juvenile arthritis is considered to be a rare disease. There is no known cure; however, up to 75% of patients will undergo remission by late adolescence. Drugs used in the treatment of juvenile arthritis are divided into 2 major classes: (a) the nonsteroidal anti-inflammatory drugs (NSAIDs) including salicylates, naproxen, ibuprofen, fenoprofen, ketoprofen, flurbiprofen, indomethacin, sulindac, tolmetin and diclofenac, and (b) disease modifying agents which encompass drugs such as antimalarial agents, gold, methotrexate, penicillamine and sulfasalazine. In almost all the reports dealing with the pharmacokinetics of NSAIDs, the level of disease activity has not been noted. The level of activity is important since, during a flare, the plasma albumin may fall to the point that it causes a substantial and clinically significant increase in the unbound serum concentration of highly bound drugs. The relationship between the concentration of these drugs in the systemic circulation and their efficacy is not clear. However, for many of them, therapeutic drug monitoring is recommended as a means of reducing the possibility of toxic reactions. Further pharmacokinetic and -dynamic evaluations are needed for many of these drugs in juvenile arthritis.

Ibuprofen: pharmacology, efficacy and safety

“…From a pharmacokinetic viewpoint there are indications that alterations in serum/plasma albumin concentrations, especially if subnormal in severe disease may affect the percentage free concentrations of NSAIDs in the circulation, which might have some toxicological or therapeutic consequences (Skeith and Jamali 1991;Furst 1992;Litalien and Jacqz-Aigrain 2001).…”

“…Adverse effects are, however, more frequent with aspirin as well as some of the other NSAIDs (indomethacin, meclofenamic acid, naproxen; Skeith and Jamali 1991) whereas these appear fewer with ibuprofen (Ansell 1983;Furst 1992).…”

“…The possible reasons for these substantial alterations in PK include decreased bioavailability (possibly from GI absorption), increased metabolic clearance and increased unbound fraction in plasma leading to increased clearance through the kidneys (Brocks and Jamali 1999). Skeith and Jamali (1991) In another study in North Carolina, USA in 38 children of both sexes age ranges 2-13 years with CF the enantiomer PKs were investigated in a single-dose, open-label investigation following 20 mg kg -1 racemic ibuprofen (Dong et al 2000). The S:R enantiomeric ratio of the plasma AUC was 2.09:1 and the free and conjugated ibuprofen in urine was 13.9:1 (S:R) which indicated there were no differences in these parameters compared with those in normal children.…”

Optimal treatment of knee monarthritis in juvenile idiopathic arthritis: A decision analysis

“…Patients in the NSAID‐only strategy received a new class of NSAIDs after each 2 month period of ineffective treatment (up to 3 different NSAIDs in the 6‐month time horizon). Each new NSAID tried at 2 month intervals was assumed to have the base‐case probability of success, regardless of previous NSAID therapy (18). NSAIDs were discontinued immediately following resolution of arthritis.…”

Non‐steroidal anti‐inflammatory drugs and slow‐acting anti‐rheumatic drugs in juvenile rheumatoid arthritis

“…The appropriate dose for children is 200 mum2 per day, not exceeding 320 mg/day.21 Very occasionally, minimal dyspepsia, rash and tennitus are reported as adverse effects of propionic acids. 22 The combination therapy of MTX and ketoprofen may induce fatal MTX intoxication with prolonged and enhanced serum concentrations in adult patients with malignant disease.23…”