Clozapine: Treat the Patient or Treat the Level?

1 RCPsych International Conference 2014yClozapine: Treat the Patient or Treat the Level? Bob FlanaganToxicology UnitClinical BiochemistryClinical BiochemistryBessemer WingDenmark HillLondon SE5 9 RSTel: 020 3299 5824 Fax: 020 3299 5825e-mail: the Level, not the Patient ,Indication for TDMDrugIndication for TDMDrugDrug not working as expected (poor adherence, inadequate Any(pqdose?)Well-defined target range, diffi lt tPhenytoinresponse difficult to assess clinically Toxic concentration associatedLithiumciclosporinToxic concentration associated with latent toxicity Lithium, ciclosporin, sirolimus, everolimus Therapeutic dose associated Clozapinewith severe toxicity in na ve subjectClozapineClozapine Effective drug, but very toxic unless used carefullyEffective drug, but very toxic unless used carefully Extremely dangerous in clozapine -na ve subject (cautious dose titration)() Idiosyncratic toxicity (bone marrow, heart, liver, etc.))

2 Narrow range of plasma concentrations associated withNarrow range of plasma concentrations associated with efficacy/minimal risk of dose-related toxicity (hyper-salivation, drowsiness, convulsions, constipation, etc.) Eliminated by hepatic metabolism: dose requirement varies dramatically depending on smoking habit (CYP1A2) thdt(CYP1A2), other drugs, etc. No plasma clozapine monitoring, no clozapineWhy clozapine TDM?yp As with all TDM need a reason for doing the testAs 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 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?

3 Has started/stopped smoking? clozapine TDM: InterpretationClozapine TDM: Interpretation < mg/L: Possible reason for poor/no mg/L: Best response/minimal AEsgp(Lower limit may be mg/L once control achieved/in elderly patients)yp) 1 mg/L: Cautious dose reduction (may lose response)?response)?(aim to bring below 1 mg/L before augmenting)1/L C tidd ti( tilt?)> 1 mg/L: Cautious dose reduction (anticonvulsant cover?)> 2 mg/L: URGENT dose reduction (anticonvulsant cover?)Summary TDM Data 1993-2007 Summary TDM Data 1993-2007(N = 104,127 from 26,796 patients)Plt ti(/L)Plasma concentration (mg/L)< < clozapine N1,534* 42,653 30,535 20,667 8,277461%1541 029 319 98004% *Sf1292f* Samples from 1259 patients; in 247 of these samples norclozapine detected at low concentration ( mg/L or less) No clozapine Detected 1993-2007: Dose (N = 998)1801541411401608794100120amples76497 18063666080No.

4 Of sa223217171012162040160<5050-100101-1501 51-200201-250251-300301-350351-400401-45 0451-500501-550551-600601-650651-700701- 750751-800801-850851-5101520253035404550 556065707580 Prescribed dose (mg/d)Inquest Told of Death at HospitalqpOxford Mail Tuesday 13 January 2009 A Patient found collapsed in a hospital bathroom may have taken a fellow Patient s drugs, an inquest heard tdtoday 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 ppconcentrations were and mg/L, respectively A fellow Patient admitted later on the day he died that he e o pa eaded a e oe day e d eda ehad shared his drugs with himClozapine PkPracticalitiesClozapine Pk -Practicalities Up to 50 x inter-individual variation in metabolic rate Very few serious drug-drug interactions-Fluvoxamine, some antibiotics (erythromycin, ciprofloxacin)

5 , carbamazepine, phenytoinOthSSRI littl /ff t-Other SSRIs little/no effect Smoking habit big effect (dose requirement 50 % on average smokers/nonsmokers)average smokers/non-smokers) clozapine clearance dose dependent (first pass saturable?)saturable?)-Basis of cautious dose titration-Basis of clozapine accumulation in some patientsBasis of clozapine accumulation in some patientsNorclozapine (N-Desmethylclozapine)p(yp) Main plasma clozapine metabolite 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 vitroreceptor binding & white cell toxicity to clozapine ) Plasma C:NC ratio (early samples sent to us) averaged across dose range (50 900+ mg/d)g(g)-C:NC ratio as important as dose and smoking status in determining plasma clozapineThe young male smoker with TRSeyou g aes o for )600700800d) ] (mg300400500se ( [ Measure Norclozapine?

6 Why Measure Norclozapine? Ensure selective assay used (important for PM work) Helps assess adherence (less short-term change than p(gclozapine) C:NC ratio (inbuilt QA)C:NC ratio (inbuilt QA)< suggests poor adherence in preceding day(s)> 3 suggests not trough sample (or inhibition ofN-> 3 suggests not trough sample (or inhibition of N-demethylation)BUT ratio saturable (normally more obvious if plasmaBUT ratio saturable (normally more obvious if plasma clozapine > 1 mg/L)Plasma clozapine /Norclozapine vs. Dosepp(Median, 10th& 90th percentiles, mg/L; N = 85,958)Dose (mg/d)NClozapineNorclozapine50-1502, ( ) ( )501502, ( ) ( )151-2508, ( ) ( )251-35018 794034(013-0 79)023(010-0 46)251-35018, ( ) ( )351-45020, ( ) ( )45155014 504045(0191 00)031(0150 60)451-55014, ( ) ( )551-65010, ( ) ( )651-7505, ( ) ( )751-8503, ( ) ( )851-1, ( ) ( )Plasma clozapine /Norclozapine vs.)))

7 Dose (di10th&90thilN898)(median, 10th& 90thpercentiles;N= 85,958)ClozapineNorclozapineTarget for ) ] ( [ (2632)(8338)(18794)(20677)(14504)(10509) (5507)(3129)(1868)Prescribed dose (mg/d) clozapine 2 mg/L 1993-2007(N461 379i)(N = 461,379 patients) ) ] ( [ [ clozapine ] (mg/L)[Cloza pine ] (mg/L)8 samples (7 patients) co-prescribed omeprazole, 7 (4 patients) co-prescribed fluvoxamine, 1 sample from Patient co-prescribed erythromycin) clozapine TDM 19932003: SummaryClozapine TDM 1993-2003: SummaryPlasma clozapine (mg/L)< < M (41,878 samples, N679*18,85512,050 7,434 2,745115(,p ,12,228 patients)% (16,294 samples, N214**5,8144,5983,702 1,8351315,143 patients)% * 566 patients ** 178 patientsA Female Non-smoker with TRSAlso prescribed aripiprazole, C:NC median (range ) (mg/L)400500g/d)1 Analyte] (300400 Dose ( [ TDM Data 1993-2003(N= 58,497)(,)Where information available: Males significantly younger (p < ): mean age males 36 yr, females 39 yr36 yr, females 39 yr Males significantly heaver (p < ): mean male weight 86 kg female 79 kg86 kg, female 79 kg Smoking habit: 71 % of males smokers, 59 % of femalesClozapine 1993-2003: DoseMaleFemalep(Median, 10 90thpercentile, N = 32,082)5,99617,6205,576700800)MaleFemale 3,290500600700se (mg/d)300400500bed Dos100200300 Prescrib0 SmokerNon Smoker(p < ) (p < ) clozapine 1993-2003: Plasma Clozapinepp(Median, 10 90thpercentile, N = 34,530)14 MaleFemale7,1953,9305, )17,7425, ] ( [ Smoker(p < ) (p < ) clozapine TDM.

8 Summarypy Treat the level: If nothing there! If > 2 mg/L!Tt th ll AND thtit Treat the level AND the Patient If poor adherence/too low a dose confirmed (< mg/L)If AE lik ll t d t ll (ll >0 5/L) If AE likely related to level (usually > mg/L) If >1 mg/L attempt cautious dose reduction even if good response and no AEsresponse and no AEs Treat the Patient (taking into account the level) If mg/L, no AEs, good response leave alone!ggp If > mg/L, no AEs, good response it If augmentation considered, bring level < 1 mg/L before adding new drugFurther ReadingFurther Reading Flanagan RJ. A practical approach to clozapine therapeuticFlanagan RJ. A practical approach to clozapine therapeutic drug Bulletin 2010; Issue 2 (June): 4-5. Flanagan RJ. clozapine therapeutic drug monitoring.

9 Why is it important to monitor clozapine doses effectively? Br J Clin Pharmac 2011; 3: 18-20. MacCall CAet alClozapine: More than 900 mg/d may be MacCall CA, et al. clozapine : More than 900 mg/d may be needed. J Psychopharmacol2008 23; 206-10 Rostami-HodjeganAet alInfluence of dose cigarette smok-RostamiHodjeganA, et al. Influence of dose, cigarette smoking, age, sex and metabolic activity on plasma clozapine concentrations. J Clin Psychopharmacol2004; 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 Monitoringand other factors: Data from a Therapeutic Drug Monitoring service, 1993-2007. Ther Drug Monit2010; 32: 438-47 More ReadingMore Reading Flanagan RJ, Ball RY. Gastrointestinal hypomotility: An under-recognised lifethreatening adverse effect of clozapinerecognised life-threatening adverse effect of clozapine .

10 Forensic Sci Int2011; 206: e31-6. Couchman L et al Plasma clozapine and norclozapine in Couchman L, et al. Plasma clozapine and norclozapine in patients prescribed different brands of clozapine (Clozaril , Denzapine , and Zaponex ). Ther Drug Monit2010; 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<18 years: Data from a Therapeutic Drug Monitoring service, 1994-2010. Early Interven Psychiatr 2013; 7: 122-30.