Table 1.

Pharmacokinetics and myopathy findings

Dose regimenCmax ± SD (μg/ml)AUC0–24 ± SD (μg · h/ml)Day 8 CPK activity ± SD (U/liter)aIncidence and severity of microscopic findings
Skeletal muscle (including diaphragm)Heart: no. of sites with myofiber degeneration total number of sites
No. of sites with myofiber degeneration-regeneration/ total no. of sitesSeverityb
Study A
 Control (saline q8h)265 ± 1821/28Minimal0/4
 25 mg/kg q24h165 ± 44682 ± 44994 ± 1,4013/28Minimal0/4
 75 mg/kg q24h540 ± 1121,840 ± 374991 ± 4218/28cMinimal0/4
 25 mg/kg q8h238 ± 222,526 ± 1973,996 ± 3,151d15/28c, eMinimal0/4
Study B
 Control (saline q8h)152 ± 230/280/4
 5 mg/kg q24h58 ± 6180 ± 42157 ± 304/28Extremely minimal; NOELf0/4
 5 mg/kg q8h58 ± 7412 ± 78483 ± 55321/28c, gExtremely minimal0/4
  • a CPK values for most dogs peaked on day 8.

  • b The scarcity of lesions in study B necessitated the use of a more-sensitive severity scale than that used in study A. By standard evaluation criteria, lesions may not have been detectable in study B because the number of fibers affected was only 1 to 5 in 10,000.

  • c Significantly different from the control group at a P value of 0.05, using Fisher's exact test.

  • d Significantly different from the control group at a P value of 0.05, using Duncan's test.

  • e Significantly different from the 25-mg/kg q24h group at a P value of 0.05, using Fisher's exact test.

  • f NOEL, no-observable-effect level. The severity and incidence of lesions at 5 mg/kg q24h are considered comparable to those for the historical controls.

  • g Significantly different from the 5-mg/kg q24h group at a P value of 0.05, using Fisher's exact test.