RCPsych International Conference 2014 Clozapine: Treat the Patient or Treat the Level? Bob Flanagan Toxicology Unit Clinical Biochemistry Bessemer Wing Denmark Hill London SE5 9RS Tel: 020 3299 5824 Fax: 020 3299 5825 e-mail: robert.flanagan@nhs.net
Treat the Level, not the Patient Indication for TDM Drug not working as expected (poor adherence, inadequate dose?) Well-defined target range, response difficult to assess clinically Toxic concentration associated with latent toxicity Therapeutic dose associated with severe toxicity in naïve subject Drug Any Phenytoin Lithium, ciclosporin, sirolimus, everolimus Clozapine
Clozapine Effective drug, but very toxic unless used carefully Extremely dangerous in clozapine-naïve subject (cautious dose titration) Idiosyncratic toxicity (bone marrow, heart, liver, etc.) Narrow range of plasma concentrations associated with efficacy/minimal risk of dose-related toxicity (hypersalivation, drowsiness, convulsions, constipation, etc.) Eliminated by hepatic metabolism: dose requirement varies dramatically depending on smoking habit (CYP1A2) th d t (CYP1A2), other drugs, etc. No plasma clozapine monitoring, no clozapine
Why Clozapine TDM? As with all TDM, need a reason for doing the test Clozapine not working as expected Adherence/dose inadequate? Augment? Dose too high? Is an AE c/o likely due to clozapine? Is clozapine psychotic at higher doses/plasma concentrations? Should I be adjusting the dose because my patient has started/stopped smoking?
Clozapine TDM: Interpretation < 0.35 mg/l: Possible reason for poor/no response 0.35 0.6 mg/l: Best response/minimal AEs (Lower limit may be 0.2 mg/l once control achieved/in elderly yp patients) 0.6 1 mg/l: Cautious dose reduction (may lose response)? (aim to bring below 1 mg/l before augmenting) > 1 mg/l: Cautious dose reduction (anticonvulsant t cover?) > 2 mg/l: URGENT dose reduction (anticonvulsant cover?)
Summary TDM Data 1993-2007 (N = 104,127 from 26,796 patients) Plasma concentration ti (mg/l) <0.01 <0.35 0.35 0.6 1.00 2.0 Clozapine N 1,534* 42,653 30,535 20,667 8,277 461 % 15 1.5 41.0 29.3 19.99 80 8.0 04 0.4 * S f 12 9 2 f * Samples from 1259 patients; in 247 of these samples norclozapine detected at low concentration (0.05 mg/l or less)
No Clozapine Detected 1993-2007: Dose (N = 998) 180 160 140 154 141 120 100 94 87 76 80 80 71 63 66 60 49 40 20 0 32 22 17 17 10 12 1 6 <50 50-100 101-150 151-200 201-250 251-300 301-350 351-400 401-450 451-500 501-550 551-600 601-650 651-700 701-750 751-800 801-850 851- Prescribed dose (mg/d) No. of samples
Inquest Told of Death at Hospital Oxford Mail Tuesday 13 January 2009 A patient found collapsed in a hospital bathroom may have taken a fellow patient s drugs, an inquest heard today Tests after his death found a potentially fatal amount of clozapine, a drug he had never been prescribed Post mortem femoral blood clozapine and norclozapine concentrations were 0.48 and 0.20 mg/l, respectively A fellow patient admitted later on the day he died that he e o pa e ad ed a e o e day e d ed a e had shared his drugs with him
Clozapine Pk - Practicalities Up to 50 x inter-individual variation in metabolic rate Very few serious drug-drug interactions - Fluvoxamine, some antibiotics (erythromycin, ciprofloxacin), carbamazepine, phenytoin - Other SSRIs little/no effect Smoking habit big effect (dose requirement ± 50 % on average smokers/non-smokers) smokers) Clozapine clearance dose dependent (first pass saturable?) - Basis of cautious dose titration - Basis of clozapine accumulation in some patients
Norclozapine (N-Desmethylclozapine) Main plasma clozapine metabolite Has longer plasma half-life than clozapine More may accumulate in tissue (possibly even in brain) than clozapine May have antipsychotic activity (has similar in vitro receptor binding & white cell toxicity to clozapine) Plasma C:NC ratio (early samples sent to us) averaged 1.33 across dose range (50 900+ mg/d) g ( g ) - C:NC ratio as important as dose and smoking status in determining plasma clozapine
The eyou young male aesmoker with TRS Clozapine Norclozapine Dose Target for clozapine 0.45 800 0.40 700 0.35 600 030 0.30 500 0.25 400 0.20 300 0.15 0.10 200 0.05 100 0.00 0 [Analyte] (mg/l) Dose (mg/d) 06/03 07/03 08/03 10/03 11/03 12/03 01/04 03/04 04/04 05/04 06/04
Why Measure Norclozapine? Ensure selective assay used (important for PM work) Helps assess adherence (less short-term change than clozapine) C:NC ratio (inbuilt QA) < 0.5 suggests poor adherence in preceding day(s) > 3 suggests not trough sample (or inhibition of N- demethylation) BUT ratio saturable (normally more obvious if plasma clozapine > 1 mg/l)
Plasma Clozapine/Norclozapine p vs. Dose (Median, 10 th & 90 th percentiles, mg/l; N = 85,958) Dose (mg/d) N Clozapine Norclozapine 50-150 2,632 0.20 (0.06-0.55) 0.55) 0.13 (0.05-0.28) 0.28) 151-250 8,338 0.30 (0.09-0.72) 0.19 (0.08-0.38) 251-350 18,794 0.34(0.13-0.79) 0.23(0.10-0.46) 351-450 20,677 0.40 (0.16-0.90) 0.27 (0.12-0.53) 451-550550 14,504 045(0191 0.45 (0.19-1.00) 00) 031(0150 0.31 (0.15-0.60) 551-650 10,509 0.50 (0.22-1.08) 0.35 (0.16-0.67) 651-750 5,507 0.54 (0.23-1.16) 0.37 (0.18-0.72) 751-850 3,129 0.57 (0.25-1.25) 0.39 (0.19-0.80) 851-1,868 0.55 (0.25-1.24) 0.41 (0.19-0.84)
Plasma Clozapine/Norclozapine vs. Dose (median, 10 th &90 th percentiles; N = 85,958) 8) Clozapine Norclozapine Target for clozapine g/l) nalyte] (m [A 1.3 1.2 1.1 1 0.9 0.8 0.7 0.6 0.5 05 0.4 0.3 0.2 0.1 0 50-151- 251-351- 451-551- 651-751- 851- (2632) (8338) (18794) (20677) (14504) (10509) (5507) (3129) (1868) Prescribed dose (mg/d)
2.5 Clozapine 2 mg/l 1993-2007 (N = 461,379 patients) [No orclozap pine] (m mg/l) 2 1.5 1 0.5 0 2 2.5 3 3.5 4 4.5 5 [Clozapine] (mg/l) 8 samples (7 patients) co-prescribed omeprazole, 7 (4 patients) co-prescribed fluvoxamine, 1 sample from patient co-prescribed erythromycin)
Clozapine TDM 1993-2003: Summary Plasma clozapine (mg/l) <0.01 <0.35 0.35 0.60 1.0 2.0 M (41,878 samples, N 679* 18,855 12,050 7,434 2,745 115 12,228 patients) % 1.6 45.0 28.8 17.8 6.6 0.3 F (16,294 samples, N 214** 5,814 4,598 3,702 1,835 131 5,143 patients) % 1.3 35.7 28.2 22.7 11.3 0.8 * 566 patients ** 178 patients
A Female Non-smoker with TRS Also prescribed aripiprazole, C:NC median 3.0 (range 2.5 3.9) 25 2.5 700 Clozapine Norclozapine Dose 2 1.5 1 0.5 600 500 400 300 200 100 [Analyte] (mg/l) Dose (mg/d) 06.04.201 010 12.04.201 010 19.04.201 010010 26.04.201 04.05.201 010 10.05.201 010010 17.05.201 24.05.201 010 01.06.201 010010 07.06.201 14.06.201 010 21.06.201 010010 28.06.201 05.07.201 010010 12.07.201 19.07.201 010 26.07.201 010010 02.08.201 23.08.201 010 20.09.201 010010 18.10.201 15.11.201 010 13.12.201 010011 10.01.201 07.02.201 011 27.06.201 011 0 0
Clozapine TDM Data 1993-2003 (N = 58,497) Where information available: Males significantly younger (p < 0.01): mean age males 36 yr, females 39 yr Males significantly heaver (p < 0.01): mean male weight 86 kg, female 79 kg Smoking habit: 71 % of males smokers, 59 % of females
Prescrib bed Dos se (mg/d) 800 700 600 500 400 300 200 100 0 Clozapine 1993-2003: Dose (Median, 10 90 th percentile, N = 32,082) Male Female 17,620 5,576 5,996 3,290 Smoker Non Smoker (p < 0.01) (p < 0.01)
Clozapine 1993-2003: Plasma Clozapine (Median, 10 90 th percentile, N = 34,530) Male Female ne] (mg/ /L) [Clozapi 14 1.4 1.2 1 0.8 0.6 0.4 0.2 17,742 5,662 7,195 3,930 0 Smoker Non Smoker (p < 0.01) (p < 0.01)
Clozapine TDM: Summary Treat the level: If nothing there! If > 2 mg/l! Treat the level l AND the patient t If poor adherence/too low a dose confirmed (< 0.35 mg/l) If AE likely l related to level l (usually >0.5 mg/l) If >1 mg/l attempt cautious dose reduction even if good response and no AEs Treat the patient (taking into account the level) If 0.35 0.6 mg/l, no AEs, good response leave alone! If >0.6 mg/l, no AEs, good response it depends If augmentation considered, bring level < 1 mg/l before adding new drug
Further Reading Flanagan RJ. A practical approach to clozapine therapeutic drug monitoring. CMHP Bulletin 2010; Issue 2 (June): 4-5. Flanagan RJ. Clozapine therapeutic drug monitoring. Why is it important to monitor clozapine doses effectively? Br J Clin Pharmac 2011; 3: 18-20. MacCall CA, et al. Clozapine: More than 900 mg/d may be needed. J Psychopharmacol 2008 23; 206-10 Rostami-Hodjegan A, et al. Influence of dose, cigarette smok- ing, age, sex and metabolic activity on plasma clozapine concentrations. J Clin Psychopharmacol 2004; 24: 70-78 Couchman L, et al. Plasma clozapine, norclozapine, and the clozapine:norclozapine ratio in relation to prescribed dose and other factors: Data from a Therapeutic Drug Monitoring service, 1993-2007. Ther Drug Monit 2010; 32: 438-47
More Reading Flanagan RJ, Ball RY. Gastrointestinal hypomotility: An under- recognised life-threatening adverse effect of clozapine. Forensic Sci Int 2011; 206: e31-6. Couchman L, et al. Plasma clozapine and norclozapine in patients prescribed different brands of clozapine (Clozaril, Denzapine, and Zaponex ). Ther Drug Monit 2010; 32: 624-7 Bowskill S, et al. Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged 65 years and over: Data from a Therapeutic Drug Monitoring service, 1996-2010. Hum Psychopharmacol Clin Exp 2012; 27: 277-83. Couchman L, et al. Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged <18 years: Data from a Therapeutic Drug Monitoring service, 1994-2010. Early Interven Psychiatr 2013; 7: 122-30.