Presentation from the International Congress of the Royal College of Psychiatrists 24-27 June 2014, London

1. RCPsych International Conference 2014y
Clozapine: Treat the Patient or
Treat the Level?
Bob Flanagan
Toxicology Unit
Clinical BiochemistryClinical Biochemistry
Bessemer Wing
Denmark Hill
London SE5 9RS
Tel: 020 3299 5824
Fax: 020 3299 5825
e-mail: robert.flanagan@nhs.net

2. Treat the Level, not the Patient,
Indication for TDM DrugIndication for TDM Drug
Drug not working as expected
(poor adherence, inadequate
Any
(p q
dose?)
Well-defined target range,
diffi lt t
Phenytoin
response difficult to assess
clinically
‘Toxic concentration’ associated Lithium ciclosporinToxic concentration associated
with latent toxicity
Lithium, ciclosporin,
sirolimus, everolimus
‘Therapeutic’ dose associated Clozapine
with severe toxicity in naïve
subject

3. 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

4. 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?

5. 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?)

6. 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)

7. No Clozapine Detected 1993-2007:
Dose (N = 998)
180
154
141
140
160
87
94100
120
amples
76
49
71
80
63 66
60
80
No.ofsa
22
32
17 17
10 12
1
6
20
40
1
6
0
<5050-100101-150151-200201-250251-300301-350351-400401-450451-500501-550551-600601-650651-700701-750751-800801-850
851-
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
Prescribed dose (mg/d)

8. Inquest Told of Death at Hospitalq p
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
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 norclozapinep p
concentrations were 0.48 and 0.20 mg/L, respectively
• A fellow patient admitted later on the day he died that hee o pa e ad ed a e o e day e d ed a e
had shared his drugs with him

9. 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, phenytoin
Oth 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

10. 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 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

11. The young male smoker with TRSe you g a e s o e S
0.45 800
Clozapine Norclozapine Dose Target for clozapine
0 30
0.35
0.40
0.45
g/L)
600
700
800
d)
0.20
0.25
0.30
lyte](mg
300
400
500
se(mg/d
0.05
0.10
0.15
[Anal
100
200
300
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

12. Why Measure Norclozapine?Why Measure Norclozapine?
• Ensure selective assay used (important for PM work)
• Helps assess adherence (less short-term change thanp ( g
clozapine)
• 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)

13. 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)

14. 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
nalyte](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)

15. Clozapine ≥ 2 mg/L 1993-2007
(N 461 379 i )(N = 461,379 patients)
2.5
2
mg/L)
1.5
pine](m
1
orclozap
0
0.5
[No
0
2 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)

16. 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 1,835 131
5,143 patients) % 1.3 35.7 28.2 22.7 11.3 0.8
* 566 patients ** 178 patients

17. A Female Non-smoker with TRS
Also prescribed aripiprazole, C:NC median 3.0 (range 2.5–3.9)
2 5 700
2
2.5
600
700
Clozapine Norclozapine Dose
1.5
2
(mg/L)
400
500
g/d)
1
Analyte](
300
400
Dose(mg
0.5
[A
100
200
0
010010010010010010010010010010010010010010010010010010010010010010010011011011
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

18. 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

19. Clozapine 1993-2003: Dose
Male Female
p
(Median, 10–90th percentile, N = 32,082)
5,996
17,620
5,576
700
800
)
Male Female
3,290
500
600
700
se(mg/d)
300
400
500
bedDos
100
200
300
Prescrib
0
Smoker Non Smoker
(p < 0.01) (p < 0.01)

20. Clozapine 1993-2003: Plasma Clozapinep p
(Median, 10–90th percentile, N = 34,530)
1 4
Male Female
7,195
3,930
5,6621
1.2
1.4
/L)
17,742
5,662
0.8
1
ne](mg/
0.4
0.6
[Clozapi
0
0.2
Smoker Non Smoker
(p < 0.01) (p < 0.01)

21. 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

22. 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 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 Monitoringand other factors: Data from a Therapeutic Drug Monitoring
service, 1993-2007. Ther Drug Monit 2010; 32: 438-47

23. 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.