Two cases of high serum clozapine concentrations occurring during inflammation in Chinese patients

Abstract

Objective Serious infections or inflammations have been associated with serum clozapine concentration increases and sometimes with clozapine toxicity. Method These two cases describe Chinese patients (Case 1: a 57-year-old female nonsmoker with severe dermatitis and Case 2: a 47-year-old male nonsmoker with influenza and secondary infection). Results In both cases, the Drug Interaction Probability Scale established the presence of a probable drug-drug interaction. In both cases, the clozapine and the total clozapine concentration-to-dose ratios followed a temporal pattern (normal-high-normal), consistent with an inhibition of clozapine metabolism during peak inflammation. In the first case, the total clozapine concentration-to-dose ratio (8 with no/low inflammation: median of 3.10 and 2 at peak inflammation: median of 3.90) provided a significant difference (P = 0.044). In the second patient, because of the smaller sample size and reduced statistical power (4 with no infection: a median of 1.59 and 2 at peak infection: 3.46), the increase did not reach significance (P = 0.13). In the first case, the median baseline clozapine concentration-to-dose ratio increased by a factor of 1.45 from 2.00 to a peak of 2.89. To compensate for the inhibition of clozapine metabolism, the dose correction factor was 0.69 (1/1.45) or a decrease in dose of approximately one-third. In the second case, the median baseline clozapine concentration-to-dose ratio increased by a factor of 2.56 from 1.15 to a peak of 2.94. Conclusion This provided a dose correction factor of 0.40 (1/2.56) or approximately half the dose, similar to published cases in Caucasians with serious respiratory infections.

Clozapine is strongly associated with the risk of pneumonia and inflammation

“…A doubling of the concentration was only observed when there was an elevation of the serum C-reactive protein (CRP) and widespread effect on the skin all over the body. 11 In a recent retrospective review of 131 clozapine inpatients at Beijing Anding Hospital, we found 18 episodes of infections/ inflammations in 16 patients. At the total sample level, these episodes: (1) extended for 2% (482/24 789) of clozapine days and (2) contaminated 3% (46/1384) of trough steady-state serum concentrations of clozapine.…”

“…10 There are also published clozapine intoxications during severe inflammation without infection. 11 More recently, in a Beijing hospital, three cases of clozapine intoxication we identified included ones with pneumonia, 12 influenza 11 and dermatitis in the absence of infection. 11 In these three Chinese patients severe infections were associated with roughly double the serum concentrations, 11 12 while the effects in relation to dermatitis depended more on its severity.…”

“…11 More recently, in a Beijing hospital, three cases of clozapine intoxication we identified included ones with pneumonia, 12 influenza 11 and dermatitis in the absence of infection. 11 In these three Chinese patients severe infections were associated with roughly double the serum concentrations, 11 12 while the effects in relation to dermatitis depended more on its severity. A doubling of the concentration was only observed when there was an elevation of the serum C-reactive protein (CRP) and widespread effect on the skin all over the body.…”

“…(1) no clinically relevant effects on the serum clozapine concentrations in the 11% of infection episodes which presented with no leukocytosis or CRP elevations; (2) halving the clozapine dose would be advisable in 61% of the infection episodes; and (3) reducing the clozapine dose to one-third would be advisable in 28% of infection episodes. 13 Therefore, based on the US 8 14 and Chinese experiences [11][12][13] as well as on the literature, 10 we proposed that clinicians need to be very alert regarding clozapine patients' risk of clozapine intoxications during any kind of systemic inflammation associated with fever and/or CRP elevations. Until better data is available, based on our experience in the US and China, we have developed three sets of recommendations regarding infection, based on timeframe: (1) prevention; (2) during the infection; and (3) after the infection.…”

Inflammation and clozapine concentrations

“…The mechanism of infection‐related changes in clozapine pharmacokinetics is thought to be related to release of inflammatory cytokines that act as inhibitors of cytochrome P‐450 enzymes 3 , 4 . Two recent case reports discussed the occurrence of elevated serum clozapine concentrations in patients with inflammatory conditions 5 …”