RCPsych International Conference 2014y

Clozapine: Treat the Patient or Treat the Level?

Bob Flanagan

Toxicology UnitClinical BiochemistryClinical BiochemistryBessemer WingDenmark HillLondon SE5 9RS

Tel: 020 3299 5824Fax: 020 3299 5825e-mail: robert.flanagan@nhs.net

Treat the Level, not the Patient,

Indication for TDM DrugIndication for TDM DrugDrug not working as expected (poor adherence, inadequate

Any(p qdose?)Well-defined target range,

diffi lt tPhenytoin

response difficult to assess clinically‘Toxic concentration’ associated Lithium ciclosporinToxic concentration associated with latent toxicity

Lithium, ciclosporin, sirolimus, everolimus

‘Therapeutic’ dose associated Clozapinewith severe toxicity in naïve subject

ClozapineClozapine• Effective drug, but very toxic unless used carefullyEffective 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 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) th d t(CYP1A2), other drugs, etc.

• No plasma clozapine monitoring, no clozapine

Why Clozapine TDM?y p

• 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?has started/stopped smoking?

Clozapine TDM: InterpretationClozapine TDM: Interpretation

< 0.35 mg/L: Possible reason for poor/no response

0.35–0.6 mg/L: Best response/minimal AEsg p

(Lower limit may be 0.2 mg/L once control achieved/in elderly patients)y p )

0.6–1 mg/L: Cautious dose reduction (may lose response)?response)?

(aim to bring below 1 mg/L before augmenting)

1 /L C ti d d ti ( ti l t ?)> 1 mg/L: Cautious dose reduction (anticonvulsant cover?)

> 2 mg/L: URGENT dose reduction (anticonvulsant cover?)

Summary TDM Data 1993-2007Summary TDM Data 1993-2007(N = 104,127 from 26,796 patients)

Pl t ti ( /L)Plasma concentration (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

% 1 5 41 0 29 3 19 9 8 0 0 4% 1.5 41.0 29.3 19.9 8.0 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

154

141140

160

8794100

120

ampl

es

76

49

7180

63 66

60

80

No.

of s

a

2232

17 1710 12

1 620

40

1 6

0

<5050

-100

101-1

5015

1-200

201-2

5025

1-300

301-3

5035

1-400

401-4

5045

1-500

501-5

5055

1-600

601-6

5065

1-700

701-7

5075

1-800

801-8

5085

1-

5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80

Prescribed dose (mg/d)

Inquest Told of Death at Hospitalq pOxford Mail Tuesday 13 January 2009

• A patient found collapsed in a hospital bathroom may have taken a fellow patient’s drugs, an inquest heard t dtoday

• 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 p pconcentrations 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 ehad shared his drugs with him

Clozapine Pk PracticalitiesClozapine Pk - Practicalities

• Up to 50 x inter-individual variation in metabolic rate• Very few serious drug-drug interactions

- Fluvoxamine, some antibiotics (erythromycin, ciprofloxacin), carbamazepine, phenytoinOth SSRI littl / ff t- Other SSRIs little/no effect

• Smoking habit big effect (dose requirement ± 50 % on average smokers/non smokers)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 patients

Norclozapine (N-Desmethylclozapine)p ( y p )

• 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 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 young male smoker with TRSe you g a e s o e S

0.45 800

Clozapine Norclozapine Dose Target for clozapine

0 300.350.400.45

g/L) 600

700800

d)

0.200.250.30

lyte

] (m

g

300400500

se (m

g/d

0.050.100.15

[Ana

l

100200300

Dos

0.00

06/03

07/03

08/03

10/03

11/03

12/03

01/04

03/04

04/04

05/04

06/04

0

06 07 08 10 11 12 01 03 04 05 06

Why Measure Norclozapine?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)< 0.5 suggests poor adherence in preceding day(s)> 3 suggests not ‘trough’ sample (or inhibition of N-> 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. Dosep p(Median, 10th & 90th percentiles, mg/L; N = 85,958)

Dose (mg/d) N Clozapine Norclozapine

50-150 2,632 0.20 (0.06-0.55) 0.13 (0.05-0.28)50 150 2,632 0.20 (0.06 0.55) 0.13 (0.05 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)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)

451 550 14 504 0 45 (0 19 1 00) 0 31 (0 15 0 60)451-550 14,504 0.45 (0.19-1.00) 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 ( di 10th & 90th il N 8 9 8)(median, 10th & 90th percentiles; N = 85,958)

Clozapine Norclozapine Target for clozapine

1.1

1.2

1.3

0.8

0.9

1

g/L)

0.5

0.6

0.7

naly

te] (

m

0.2

0.3

0.4

0 5

[A

0

0.1

0.2

50- 151- 251- 351- 451- 551- 651- 751- 851-(2632) (8338) (18794) (20677) (14504) (10509) (5507) (3129) (1868)

Prescribed dose (mg/d)

Clozapine ≥ 2 mg/L 1993-2007(N 461 379 i )(N = 461,379 patients)

2.5

2

mg/

L)

1.5

pine

] (m

1

orcl

ozap

0

0.5[No

02 2.5 3 3.5 4 4.5 5

[Clozapine] (mg/L)[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: SummaryClozapine 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( , p ,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 1315,143 patients) % 1.3 35.7 28.2 22.7 11.3 0.8

*  566 patients              ** 178 patients

A Female Non-smoker with TRSAlso prescribed aripiprazole, C:NC median 3.0 (range 2.5–3.9)

2 5 700

2

2.5

600

700Clozapine Norclozapine Dose

1.5

2

(mg/

L)

400

500

g/d)

1

Ana

lyte

] (

300

400

Dos

e (m

g

0.5

[A

100

200

0

010

010

010

010

010

010

010

010

010

010

010

010

010

010

010

010

010

010

010

010

010

010

010

011

011

011

0

06.04

.201

12.04

.201

19.04

.201

26.04

.201

04.05

.201

10.05

.201

17.05

.201

24.05

.201

01.06

.201

07.06

.201

14.06

.201

21.06

.201

28.06

.201

05.07

.201

12.07

.201

19.07

.201

26.07

.201

02.08

.201

23.08

.201

20.09

.201

18.10

.201

15.11

.201

13.12

.201

10.01

.201

07.02

.201

27.06

.201

Clozapine TDM Data 1993-2003(N = 58,497)( , )

Where information available:

• Males significantly younger (p < 0.01): mean age males 36 yr, females 39 yr36 yr, females 39 yr

• Males significantly heaver (p < 0.01): mean male weight 86 kg female 79 kg86 kg, female 79 kg

• Smoking habit: 71 % of males smokers, 59 % of females

Clozapine 1993-2003: Dose

Male Female

p(Median, 10–90th percentile, N = 32,082)

5,99617,620

5,576700

800

)

Male Female

3,290

500

600

700

se (m

g/d)

300

400

500

bed

Dos

100

200

300

Pres

crib

0

Smoker Non Smoker(p < 0.01) (p < 0.01)

Clozapine 1993-2003: Plasma Clozapinep p(Median, 10–90th percentile, N = 34,530)

1 4

Male Female

7,1953,930

5,6621

1.2

1.4

/L)

17,7425,662

0.8

1

ne] (

mg/

0.4

0.6

[Clo

zapi

0

0.2

Smoker Non Smoker(p < 0.01) (p < 0.01)

Clozapine TDM: Summaryp y• Treat the level:

– If nothing there!– If > 2 mg/L!

T t th l l AND th ti t• Treat the level AND the patient– If poor adherence/too low a dose confirmed (< 0.35 mg/L)

If AE lik l l t d t l l ( ll >0 5 /L)– If AE likely related to level (usually >0.5 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 0.35–0.6 mg/L, no AEs, good response – leave alone!g g p– If >0.6 mg/L, no AEs, good response – it depends…– If augmentation considered, bring level < 1 mg/L before

adding new drug

Further ReadingFurther Reading• Flanagan RJ. A practical approach to clozapine therapeuticFlanagan 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• 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-Rostami Hodjegan A, et al. Influence of dose, cigarette smoking, 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 Monitoringand other factors: Data from a Therapeutic Drug Monitoring service, 1993-2007. Ther Drug Monit 2010; 32: 438-47

More ReadingMore Reading• Flanagan RJ, Ball RY. Gastrointestinal hypomotility: An under-

recognised life threatening adverse effect of clozapinerecognised life-threatening adverse effect of clozapine. Forensic Sci Int 2011; 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 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<18 years: Data from a Therapeutic Drug Monitoring service, 1994-2010. Early Interven Psychiatr 2013; 7: 122-30.