clozapine case 4: perphenazine 1-02-16 -...
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Clozapine Case 4:
Perphenazine
1-02-16
Jose de Leon, MD
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4. Clozapine Case 4
J Clin Psychiatry 1999;60:710
by Cooke C & de Leon J
http://www.ncbi.nlm.nih.gov/pubmed/10549694
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Educational Objectives
At the conclusion of this presentation, the
participant should be able to:
1. Think about pharmacological principles in the context of polypharmacy.
2. Appreciate that for understanding clozapine
safety, one must consider:
2.1. Personal, environmental and genetic
factors.
2.2. Pharmacodynamics and pharmacokinetics.
3. Summarize how to use clozapine levels in clinical practice.
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Abbreviations
■ α: alpha, one of two types of adrenergic receptors
■ ADR: adverse drug reaction
■ C: concentration
■ C/D: concentration-to-dose ratio
■ CYP: cytochrome P450
■ D: dose
■ DDI: drug-drug Interaction
■ FMO: flavin-containing monooxygenase
■ M: muscarinic (two types of cholinergic receptors:
□ muscarinic, and
□ nicotinic)
■ PM: poor metabolizer
■ RCT: randomized controlled trial
■ TDM: therapeutic drug monitoring
■ UGT: uridine 5-diphosphate glucuronosyltransferase
■ UM: ultrarapid metabolizer
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Receptor Terminology
■ Allosteric Regulation:
The modification of the reactivity of
ENZYMES by the binding of effectors
to sites (ALLOSTERIC SITES) on the
enzymes other than the substrate
BINDING SITES
http://www.ncbi.nlm.nih.gov/mesh?term=allosteric%20regulation
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Clozapine Case 44.0. Introduction
4.1. Clozapine Metabolism
4.2. Baseline Clozapine TDM
4.3. Adding Perphenazine
4.4. Clozapine TDM Follow-up
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Clozapine Case 44.0. Introduction
4.0.1. Description
4.0.2. Questions
4.1. Clozapine Metabolism
4.1.1. Metabolic Enzymes
4.1.2. Genetic, Environmental and Personal Variables
4.2. Baseline Clozapine TDM
4.2.1. First Clozapine TDM
4.2.2. All Baseline Clozapine TDM
4.3. Adding Perphenazine
4.3.1. Clinical Outcome
4.3.2. Next Course of Action
4.3.3. Intervention
4.4. Clozapine TDM Follow-up
4.4.1. Medication Changes
4.4.2. Clozapine TDM Follow-up
4.4.3. Interpretation
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4.0. Introduction
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4.0. Case 4: Introduction
4.0.1. Description
4.0.2. Questions
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4.0.1. Introduction: Description
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4.0.1. Clozapine Case 4: Description
■ C.C. Cooke, MD, was a resident who rotated
for 1 month on Dr. de Leon’s unit for treatment-
refractory patients.
■ She helped with the publication of this
peculiar clozapine DDI during a 1-month
clinical rotation.
■ The patient asked to be on perphenazine.
Dr. de Leon thought the patient was stable on
haloperidol augmentation of clozapine but he
agreed to comply with request to avoid non-
compliance and proposed switching the patient
from haloperidol to perphenazine.
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4.0.1. Clozapine Case 4: Description
■ 46-year-old Caucasian ♂ with schizoaffective
disorder
■ History of very serious violence toward female
nurses when not compliant with medication
■ Clozapine D ranged between 400-500 mg/day
■ Taking other meds:
□ haloperidol: 15 mg/day for 6 months
□ valproic acid: 3000 mg/day for
schizoaffective disorder and violence
□ benztropine: 9 mg/day (hypersalivation)
□ clonazepam: 1 mg/day (unknown indication;
patient refused to discuss discontinuation).
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4.0.2. Introduction: Questions
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4.0.2. Clozapine Case 4: Questions
Do you need to ask any
questions to be able to
interpret clozapine C?
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4.0.2. Clozapine Case 4: Questions
Do you need to ask any
questions to be able to
interpret clozapine C?
Yes, several questions
are important.
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4.0.2. Clozapine Case 4: Questions
Which questions?
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4.0.2. Clozapine Case 4: Questions
First, “sample issues”,
that are important for all TDM Cs.
Were all Cs:
1) measured at the same lab,
2) Cs at steady state,
and 3) trough Cs?
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4.0.2. Clozapine Case 4: Questions
First, “sample issues”,
that are important for all TDM Cs.
Were all Cs:
1) measured at the same lab,
2) Cs at steady state,
and 3) trough Cs?
Yes, all Cs were measured
1) at the same laboratory,
2) at least 1 week after clozapine
(or any medication change), and
3) early in the morning (before meds).
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4.0.2. Clozapine Case 4: QuestionsRemember, for interpreting all TDMs
there are three “sample” issues
that are important:
1) different labs use different techniques that may
provide different results.
Try to use the same lab for a patient’s Cs.
2) always draw Cs at steady state, and
3) Cs vary through the day.
Order trough Cs in the early morning
before any medication is given.
The concept of half-life is important and
is discussed in Clozapine Case 6: Half-Life.
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4.0.2. Clozapine Case 4: Questions
Second, was the patient
smoking?
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4.0.2. Clozapine Case 4: Questions
Second, was the patient
smoking?
Yes, he was a stable smoker
of 10 cigarettes/day,
which were controlled by
staff. Smoking may cause a
mild induction of
clozapine metabolism.
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4.0.2. Clozapine Case 4: Questions
Third, was he consuming any
caffeine?
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4.0.2. Clozapine Case 4: Questions
Third, was he consuming any
caffeine?
No, he had no unit access to
caffeinated beverages
and could only leave the unit
when escorted by staff.
Caffeine can inhibit
clozapine metabolism.
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4.0.2. Clozapine Case 4: Questions
In summary, all Cs in this patient
were measured
in same lab,
at steady state
early morning,
with stable levels of smoking and
no access to caffeine.
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4.0.2. Clozapine Case 4: Questions
Moreover, the patient was followed
for >400 days (168 days before perphenazine and 263 after)
with >15 clozapine Cs.
It is easier
to interpret C variations
during perphenazine treatment
if you can compare Cs
before and after starting perphenazine.
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4.1. Clozapine Metabolism
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4.1. Clozapine Case 4: Clozapine Metabolism
4.1.1. Metabolic Enzymes
4.1.2. Genetic, Environmental and Personal Variables
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4.1.1. Clozapine Metabolic Enzymes
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4.1.1 Clozapine Case 4: Clozapine Metabolic Enzymes
4.1.1.1. Main Metabolic Enzyme
4.1.1.2. Main Metabolite
4.1.1.3. Metabolism in Detail
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4.1.1.1. Main Clozapine Metabolic Enzyme
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4.1.1.1.Clozapine Metabolism: CYP1A2.
■ Remember: CYP1A2 is the mainenzyme. It may account for 70% ofclozapine metabolism. http://www.ncbi.nlm.nih.gov/pubmed/7893591
■ CYP1A2 metabolizes clozapine to:□ Norclozapine (also called
desmethylclozapine).
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4.1.1.2. Main Clozapine Metabolite
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4.1.1.2. Clozapine Metabolite
■ Norclozapine: no antipsychotic activity
□ Patented by a pharmaceutical company
□ Norclozapine placebo-controlled
RCT for: ● antipsychotic efficacy or
● cognitive augmentation
were conducted but never published.
■ Norclozapine:
□ reflects clozapine metabolism, and
□ can contribute to ADRs, particularly to
antimuscarinic ADRs.
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4.1.1.2. Clozapine Metabolite
■ Clozapine and norclozapine have high affinity for
muscarinic receptors.
■ At colon: M3 receptors
Clozapine treatment is frequently associated with
constipation (a sign of M3 blockade).
A RCT indicated serum norclozapine Cs contributed to
constipation http://www.ncbi.nlm.nih.gov/pubmed/12920408
■ Clozapine frequently causes hypersalivation through
two possible mechanisms:
□ muscarinic receptors (most important):
● clozapine is a partial agonist at M1 and M3 .
● norclozapine is an allosteric agonist of M1.
□ α receptors: clozapine is an α1 antagonist.
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4.1.1.3. Clozapine Metabolism in Detail
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4.1.1.3. Clozapine Metabolism in Detail
■ Main metabolic pathway to norclozapine:
□ CYP1A2 is the most important enzyme,
□ CYP2C19 may have a greater role than previously
thought. http://www.ncbi.nlm.nih.gov/pubmed/25200585
□ CYP2D6 and CYP3A4 may have minor roles.
■ Second pathway to clozapine-N-oxide:
□ by: ● CYP3A4 and
● FMO
□ probably is a reversible pathway
■ Glucuronidation by UGTs is probably a minor pathway.
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4.1.2. Genetic, Environmental and
Personal Variables
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4.1.2. Genetic, Environmental and Personal Variables
4.1.2.1. Genetic Variables
4.1.2.2. Environmental Variables
4.1.2.3. Personal Variables
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4.1.2.1. Genetic Variables
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4.1.2.1. Clozapine Metabolism: Genetic Variables
■ CYP1A2:
□ The literature does not provide a clear description
of PMs and UMs. If they exist, they are rare (<1%).
■ CYP2C19 PMs may have lower ability to metabolize
clozapine.
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4.1.2.2. Environmental Variables
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4.1.2.2. Environmental Variables
■ Inducers: ↑ metabolism & ↓ serum Cs.
■ Inhibitors: ↓ metabolism & ↑ serum Cs.
■ Correction factor: Multiply dose by this
number to correct for the effect of the inducer
or inhibitor.
□ Inducer: correction factor >1 (e.g., 2)
□ Inhibitor: correction factor <1 (e.g., 0.5)
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4.1.2.2. Environmental Variables
4.1.2.2.1. Inducers
4.1.2.2.2. Inhibitors
4.1.2.2.3. Valproic Acid
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4.1.2.2.1. Inducers
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4.1.2.2.1. Inducers
■ Rifampin: probably very powerful
■ Potent antiepileptic drugs (correction factor 1.5-2 x):
□ carbamazepine (careful; associated with agranulocytosis)
□ phenobarbital
□ phenytoin
■ Omeprazole: (correction factor 1.5 x)
□ others from the same family: ● esomeprazole
● lansoprazole
■ Polycyclic aromatic hydrocarbons in smoke:
□ tobacco smoking: (correction factor 1.5 x)
□ cannabis smoking: may be the same
□ charbroiled food: unlikely to be relevant
□ toasted coffee: may be relevant in South Asians
■ Cruciferous vegetables (broccoli & Brussels sprouts)
are unlikely to be relevant.
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4.1.2.2.2. Inhibitors
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4.1.2.2.2. Inhibitors
4.1.2.2.2.1. Psychiatric Drugs
4.1.2.2.2.2. Non-psychiatric Drugs
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4.1.2.2.2.1. Psychiatric Inhibitors
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4.1.2.2.2.1. Psychiatric Inhibitors
■ Fluvoxamine: CYP1A2 and CYP2C9 inhibition
Very powerful: only use with TDM
Correction factor down to 0.10-0.20
■ Fluoxetine and paroxetine: mild inhibitors
Rarely clinically relevant: correction factor: 0.75-0.80
■ Sertraline may be relevant only in high doses:
see Clozapine Case 3 Presentation.
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4.1.2.2.2.2. Non-Psychiatric Inhibitors
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4.1.2.2.2.2. Non-Psychiatric Inhibitors
■ Ciprofloxacin: probably a powerful inhibitor
□ norfloxacin: also probably a CYP1A2 inhibitor
□ safe members from the family that are NOT inhibitors:
● gatifloxacin
● gemifloxacin
● levofloxacin
● moxifluxacin
● trovafloxacin
■ Oral contraceptives (estrogen) are clinically-relevant
inhibitors.
■ Amiodarone: probably a relevant inhibitor
■ Be careful with erythromycin and clarithromycin
(powerful CYP3A4 inhibitors): monitor with TDM.
■ Caffeine: correction factor 0.5 x
See Clozapine Case 1 presentation.
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4.1.2.2.3. Valproic Acid
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4.1.2.2.3. Valproic Acid
■ Valproic acid can:
□ be a mild inhibitor of clozapine
metabolism,
□ be a mild inducer of clozapine
metabolism (possibly in smokers)
http://www.ncbi.nlm.nih.gov/pubmed/24764199
□ have major inductive effects (rare)
● in sensitive patients
● dose-related (better defined as
related to the free serum valproic Cs).
See Clozapine Case 5 Presentation.
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4.1.2.3. Personal Variables
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4.1.2.3. Personal Variables■ Age: ↑ age ↓ renal excretion. Be careful in geriatric.
■ Sex: ♀: relatively lower metabolism
Partly explained by estrogens (CYP1A2 inhibitors)
Contaminated by smoking (♂ tend to smoke more)
■ Pregnancy: should ↓ metabolism but not studied
(CYP1A2/CYP2C19 inhibitor)
■ Severe inflammation/infection: ↓ metabolism
See Clozapine Case 2 Presentation
■ East Asians (Chinese, Japanese & Koreans):
↓ metabolism: □ lower CYP2C19 activity
□ unclear if lower CYP1A2 activity
See Clozapine Case 3 Presentation
■ ↑ weight associated with ↓ mild Cs in TDM studies:
Relevant: □ extreme obesity or
□ dramatic weight changes in a patient
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4.2. Baseline Clozapine TDM
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4.2. Case 4: Baseline Clozapine TDM
4.2.1. First Clozapine TDM
4.2.2. All Baseline Clozapine TDM
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4.2.1. First Clozapine TDM
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4.2.1. Clozapine Case 4: First Clozapine TDM
■ First TDM:
□ Clozapine D = 500 mg/day
□ Clozapine C = 653 ng/ml
□ Norclozapine C = 242 ng/ml
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4.2.1. Clozapine Case 4: First Clozapine TDM
What was the
clozapine C/D ratio in
this first TDM?
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4.2.1. Clozapine Case 4: First Clozapine TDM
What was the
clozapine C/D ratio in
this first TDM?
C/D=653/500=1.3.
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4.2.1. Clozapine Case 4: First Clozapine TDM
Is a clozapine C/D
ratio=1.3 normal
in a US ♂ smoker?
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4.2.1. Clozapine Case 4: First Clozapine TDM
Is a clozapine C/D
ratio=1.3 normal
in a US ♂ smoker?
Mildly abnormal in Dr.
de Leon’s experience.
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4.2.1. Clozapine Case 4: First Clozapine TDM
■ In US Caucasians, a C/D ratio:
□ >1.2 indicates poor metabolic capacity.
□ <0.6 indicates high metabolic capacity.
□ 0.6-1.2 is probably normal.
■ This is influenced by smoking:
□ ♀ non-smokers: C/D ratios ≤1.2
□ ♂ smokers: C/D ratios ≥ 0.6
□ ♀ smokers and ♂ smokers:
intermediate C/D ratios of 0/6-1.2
http://www.ncbi.nlm.nih.gov/pubmed/25200585
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4.2.2. All Baseline Clozapine TDMs
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4.2.2. All Baseline Clozapine TDMs
Day Clo D C (ng/ml) C/D Ratiomg/day Clo NorC Total Clo Total
-168 500 653 242 895 1.3 1.8
-164 500 755 274 1029 1.5 2.1
-143 400 557 185 742 1.4 1.9
-136 400 704 204 908 1.8 2.3
-108 500 823 303 1126 1.7 2.3
-73 400 621 196 817 1.6 2.0
-45 450 613 201 814 1.4 1.8
-16 450 657 181 838 1.5 1.9
Clo: clozapine; NorC: norclozapine
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4.2.2. All Baseline Clozapine TDMs
Summary of 8 TDMsRange Mean
Clozapine D (mg/day) 400-500 450
Clozapine C/D 1.3-1.8 1.5
Total Clozapine C/D 1.8-2.3 2.0
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4.2.2. All Baseline Clozapine TDMs
Is a clozapine
C/D ratio=1.3-1.8 normal
in a US ♂ smoker?
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4.2.2. All Baseline Clozapine TDMs
Is a clozapine
C/D ratio=1.3-1.8 normal
in a US ♂ smoker?
Mildly abnormal in Dr.
de Leon’s experience.
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4.2.2. All Baseline Clozapine TDMs
Why is the clozapine
C/D ratio mildly elevated?
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4.2.2. All Baseline Clozapine TDMs
Why is the clozapine
C/D ratio mildly elevated?
Probably due to the
co-medication.
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4.2.2. All Baseline Clozapine TDMs
■ Co-medications:
□ haloperidol: partly metabolized by CYP2D6
□ benztropine: possibly metabolized by
CYP2D6 (delirium has been associated with
co-prescription of CYP2D6 inhibitors)
□ clonazepam: partly metabolized by CYP3A4
□ valproic acid: may be a mild inducer (and
possibly a competitive inhibitor)
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4.3. Adding Perphenazine
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4.3. Case 4: Adding Perphenazine
4.3.1. Clinical Outcome
4.3.2. Next Course of Action
4.3.3. Intervention
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4.3.1. Perphenazine:
Clinical Outcome
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4.3.1. Clozapine Case 4: Perphenazine Outcome
■ The patient has a history of: □ severe violence due to delusions□ noncompliance in taking meds□ requests for irrational medication
changes■ The patient:
□ reports feeling better on perphenazine (in the past)
□ wants to be switched from haloperidol to perphenazine
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4.3.1. Clozapine Case 4: Perphenazine Outcome
■ Medications (clozapine 450 mg/d):
□ taken off haloperidol
□ perphenazine D:↑ 24 to 48 mg/d
■ Within the second week:
□ the patient complained of
● knee buckling and
● hypersalivation
□ psychosis worsened, and included
threatening behavior
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4.3.1. Clozapine Case 4: Perphenazine Outcome
What do neurologists call
knee buckling?
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4.3.1. Clozapine Case 4: Perphenazine Outcome
What do neurologists call
knee buckling?
Myoclonus.
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4.3.1. Clozapine Case 4: Perphenazine Outcome
The patient has myoclonus
and hypersalivation.
These 2 symptoms are
suggestive of…
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4.3.1. Clozapine Case 4: Perphenazine Outcome
The patient has myoclonus
and hypersalivation.
These 2 symptoms are
suggestive of…
Clozapine intoxication.
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4.3.1. Clozapine Case 4: Perphenazine Outcome
Worsening of psychosis
indicates…
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4.3.1. Clozapine Case 4: Perphenazine Outcome
Worsening of psychosis
indicates…
It is hard to say
(see next slide).
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4.3.1. Clozapine Case 4: Perphenazine Outcome
■ Worsening of psychosis can be a sign:
1) that perphenazine was not as effective as
haloperidol (patient was stable on
haloperidol),
and/or
2) of a clozapine intoxication.
In the experience of Dr. de Leon,
clozapine intoxication:
□ can occasionally manifest as delirium
□ but does not manifest as a pure
psychotic exacerbation without
confusion.
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4.3.1. Clozapine Case 4: Perphenazine Outcome
This is why it is important
to make only ONE
medication change at a
time, particularly in
complex patients.
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4.3.1. Clozapine Case 4: Perphenazine Outcome
■ Dr. de Leon thought adding a third
antipsychotic was not a good idea.
This is why he proposed stopping
haloperidol before adding perphenazine.
■ In retrospect, this complicated the
interpretation.
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4.3.2. Perphenazine:
Next Course of Action
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4.3.2. Clozapine Case 4: Perphenazine Next
How will you verify a
clozapine intoxication?
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4.3.2. Clozapine Case 4: Perphenazine Next
How will you verify a
clozapine intoxication?
With clozapine TDM.
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4.3.2. Clozapine Case 4: Perphenazine Next
■ During the 11th day on perphenazine
and 7 days after ↑ 48 mg/d:
□ clozapine D: 450 mg/day
□ clozapine C: 1451 ng/ml
□ norclozapine C: 484 ng/ml
□ total C: 1935 ng/ml
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4.3.2. Clozapine Case 4: Perphenazine Next
Was the
clozapine C=1461 ng/ml
compatible with a clozapine
intoxication?
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4.3.2. Clozapine Case 4: Perphenazine Next
Was the
clozapine C=1461 ng/ml
compatible with a clozapine
intoxication?
Yes, a C>1000 ng/ml is
definitively too high.The concept of clozapine C therapeutic range is
discussed in a prior presentation
(see Clozapine Case 1: The Relevance of CYP).
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4.3.2. Clozapine Case 4: Perphenazine Next
What was the
clozapine C/D ratio on
perphenazine?
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4.3.2. Clozapine Case 4: Perphenazine Next
What was the
clozapine C/D ratio on
perphenazine?
C/D=1451/450=3.2.
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4.3.2. Clozapine Case 4: Perphenazine Next
What was the
total clozapine C/D ratio on
perphenazine?
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4.3.2. Clozapine Case 4: Perphenazine Next
What was the
total clozapine C/D ratio on
perphenazine?
C/D=1935/450=4.3.
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4.3.2. Clozapine Case 4: Perphenazine Next
Day Clo D C (ng/ml) C/D Ratiomg/day Clo NorC Total Clo Total
-168 500 653 242 895 1.3 1.8
-164 500 755 274 1029 1.5 2.1
-143 400 557 185 742 1.4 1.9
-136 400 704 204 908 1.8 2.3
-108 500 823 303 1126 1.7 2.3
-73 400 621 196 817 1.6 2.0
-45 450 613 201 814 1.4 1.8
-16 450 657 181 838 1.5 1.9
11 450 1451 484 1935 3.2 4.3
Clo: clozapine; NorC: norclozapine
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4.3.2. Clozapine Case 4: Perphenazine Next
Comparison TDM
Before Perphenazine
N 8 1
Means
Clozapine C/D 1.5 3.2
Total Clozapine C/D 2.0 4.3
Ratios are increased > 2 x.
This indicates that clozapine metabolism is
decreased by half and is severely impaired.
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4.4.3. Clozapine Case 4: Diagnosis
■ 2 days later (day 13 on perphenazine)
(after refusing 350 mg night dose from
total of 450 mg/d):
□ clozapine C: 1162 ng/ml
□ norclozapine C: 469 ng/ml
□ total C: 1631 ng/ml
□ perphenazine C: 19 ng/ml
■ These clozapine Cs were not in steady state but continued to be too high.
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4.3.3. Perphenazine:
Intervention
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4.3.3. Clozapine Case 4: Intervention
Please remember we have
two problems:
1) clozapine intoxication signs
and
2) worsening of the psychosis.
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4.3.3. Clozapine Case 4: Intervention
What will you do after
seeing the TDM results to
resolve these 2 issues?
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4.3.3. Clozapine Case 4: Intervention
What will you do after
seeing the TDM results to
resolve these 2 issues?
Propose to the patient
a switch back from
perphenazine to
haloperidol.
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4.3.3. Clozapine Case 4: Intervention
■ Perphenazine was discontinued.
■ Haloperidol (15 mg/day) was restarted.
■ 8 days later:
□ clozapine C: 693 ng/ml
□ norclozapine C: 222 ng/ml
□ total C: 915 ng/ml
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4.3.3. Clozapine Case 4: Intervention
What was the
clozapine C/D ratio 8 days
after perphenazine
discontinuation?
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4.3.3. Clozapine Case 4: Intervention
What was the
clozapine C/D ratio 8 days
after perphenazine
discontinuation?
C/D=693/450=1.5.
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4.3.3. Clozapine Case 4: Intervention
What was the
total clozapine C/D ratio
8 days after perphenazine
discontinuation?
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4.3.3. Clozapine Case 4: Intervention
What was the
total clozapine C/D ratio
8 days after perphenazine
discontinuation?
C/D=915/450=2.0.
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4.3.3. Clozapine Case 4: Intervention
■ Another 2 clozapine TDMs showed
similar values.
They are described in next slide.
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4.3.2. Clozapine Case 4: Perphenazine Next
Day Clo D C (ng/ml) C/D ratiomg/day Clo NorC Total Clo Total
-168 500 653 242 895 1.3 1.8
-164 500 755 274 1029 1.5 2.1
-143 400 557 185 742 1.4 1.9
-136 400 704 204 908 1.8 2.3
-108 500 823 303 1126 1.7 2.3
-73 400 621 196 817 1.6 2.0
-45 450 613 201 814 1.4 1.8
-16 450 657 181 838 1.5 1.9
11 450 1451 484 1935 3.2 4.3
21 450 693 222 915 1.5 2.0
46 450 738 243 981 1.6 2.2
67 450 529 193 722 1.2 1.6Clo: clozapine; NorC: norclozapine
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4.3.3. Clozapine Case 4: Intervention
Comparison TDM
Before Perphenazine After
N 8 1 3 .
Mean
Clozapine C/D 1.5 3.2 1.5
Total clozapine C/D 2.0 4.3 1.9
The C/D ratios return to baseline.
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4.3.3. Clozapine Case 4: Intervention
■ The change to haloperidol was
associated with:
□ improvement of psychosis
□ disappearance of threatening behavior
□ no hypersalivation
□ no knee buckling
■ The patient agreed to 150 mg
haloperidol decanoate injection.
■ Oral haloperidol was discontinued and
haloperidol decanoate injections were
started and given every 3 weeks.
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4.4. Clozapine TDM Follow-Up
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4.4. Clozapine TDM Follow-Up
4.4.1. Medication Changes
4.4.2. Clozapine TDM Follow-up
4.4.3. Interpretation
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4.4.1. Follow-Up: Medication Changes
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4.4.1. Case 4: Follow-Up Medication Changes
■ The patient was followed-up for > 200 days:
□ He asked to be switched from benztropine
(9 mg/day) to trihexyphenidyl (4 mg/day).
□ He agreed to continue haloperidol
decanoate every 3 weeks (first 150 mg
and then 200 mg).
□ He finally agreed to clonazepam
discontinuation and
□ valproate D ↓ slightly to 2750 mg/day.
■ Medication reduction was accomplished.
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4.4.1. Case 4: Follow-Up Medication Changes
■ Before perphenazine,
clozapine D=450 mg/day had provided
clozapine Cs in 600 ng/ml, which is
clearly >350 ng/ml.
■ Dr. de Leon tried
↓ clozapine D=350 mg/day,
but Cs ranged in the low 300s ng/ml.
■ He ↑ clozapine D back to 450 mg/day,
which provided a clozapine C=433 ng/ml,
> recommended 350 ng/ml lower limit.
■ Pink values reflect medication reduction.
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4.4.2. Follow-Up: Clozapine TDM
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4.4.2. Case 4: Clozapine TDM Follow-UpDay Clo D C (ng/ml) C/D Ratio
mg/day Clo NorC Total Clo Total
-168 500 653 242 895 1.3 1.8
-164 500 755 274 1029 1.5 2.1
-143 400 557 185 742 1.4 1.9
-136 400 704 204 908 1.8 2.3
-108 500 823 303 1126 1.7 2.3
-73 400 621 196 817 1.6 2.0
-45 450 613 201 814 1.4 1.8
-16 450 657 181 838 1.5 1.9
11 450 1451 484 1935 3.2 4.3
21 450 693 222 915 1.5 2.0
46 450 738 243 981 1.6 2.2
67 450 529 193 722 1.2 1.6
123 350 327 129 456 0.9 1.3
151 350 318 126 444 0.9 1.3
179 350 311 127 438 0.9 1.3
207 350 327 129 456 0.9 1.3
263 450 433 162 595 1.0 1.3
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4.4.2. Case 4: Clozapine TDM Follow-Up
Comparison TDM
Before Perphenazine After
Med Reduction
N 8 1 5 _ _
Means
Clozapine C/D 1.5 3.2 0.9
Total clozapine C/D 2.0 4.3 1.2
After the medication reduction, the clozapine C/D ratio=0.9 (<1.2),
which is within the normal US range.
The total clozapine C/D ratio=1.2 also looks normal.
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4.4.3. Follow-Up: Interpretation
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4.4.3. Case 4: Follow-Up Interpretation
Comparison TDM
Before Perphenazine After Med
Reduction .
Clozapine Metabolism Slightly ↓ Very ↓ Normal for US
.
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4.4.3. Follow-Up: Interpretation
4.4.3.1. Before Perphenazine
4.4.3.2. On Perphenazine
4.3.3.3. After Perphenazine
4.3.3.4. Longitudinal Course of Clozapine Metabolism
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4.4.3.1. Before Perphenazine: Interpretation
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4.4.3.1. Case 4: Interpretation Before
How do you explain that
clozapine C/D ratios were
slightly ↓ before,
very ↓on perphenazine,
and normal after?
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4.4.3.1. Case 4: Interpretation Before
■ It is possible that the patient, despite being
♂ and a mild smoker, has average baseline
metabolic capacity.
■ Imagine that, before perphenazine,
clozapine metabolism was already
compromised by competitive inhibition of:
□ CYP2D6 from ● benztropine, and
● haloperidol
□ CYP3A4: clonazepam, and
□ possibly by an unknown mechanism:
valproate
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4.4.3.2. On Perphenazine: Interpretation
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4.4.3.2. Case 4: Perphenazine Interpretation
What do we know about
perphenazine metabolism?
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4.4.3.2. Case 4: Perphenazine Interpretation
■ In vivo perphenazine studies suggest: □ the most important enzyme is CYP2D6
http://www.ncbi.nlm.nih.gov/pubmed/17429316
■ In vitro study suggests other CYPsare also involved: □ CYP1A2□ CYP3A4□ CYP2C19http://www.ncbi.nlm.nih.gov/pubmed/11136295
■ Population US study: □ African-Americans: faster metabolism□ Smokers: faster metabolism
Proposed that metabolism is by CYP1A2.http://www.ncbi.nlm.nih.gov/pubmed/19843655
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4.4.3.2. Case 4: Perphenazine Interpretation
Is this relevant in this case?
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4.4.3.2. Case 4: Perphenazine Interpretation
Is this relevant in this case?
Probably yes.
Perphenazine can be a
competitive inhibitor of
CYP2D6 and perhaps
CYP1A2.
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4.4.3.2. Case 4: Perphenazine Interpretation
■ This is a patient with compromised
clozapine metabolism.
■ Perphenazine acted as a competitive
inhibitor for clozapine metabolism,
and saturated the system.
The ability to metabolize clozapine was
↓ in half when compared to baseline.
■ The concept of competitive inhibition is
explained in the Clozapine Case 3
Presentation.
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4.4.3.3. After Perphenazine: Interpretation
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4.4.3.3. Case 4: Interpretation After
How do you explain that
clozapine metabolism
normalized in the end?
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4.4.3.3. Case 4: Interpretation After
■ Several medications were changed:
□ benztropine was discontinued
(competitor for CYP2D6)
□ clonazepam was discontinued
(competitor for CYP3A4)
□ haloperidol: from oral to decanoate.
Haloperidol may compete for CYP2D6.
It is not known whether this change
(oral vs. decanoate) influences
CYP2D6 competitive inhibition or not.
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4.4.3.3. Case 4: Interpretation After
■ With these medication changes:
□ The clozapine C/D ratio become normal.
A clozapine C/D ratio=0.9, is in the middle
of the US normal range=0.6-1.2.
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4.4.3.4. Longitudinal Course of Clozapine Metabolism
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4.4.3.4. Case 4: Longitudinal Course of Clozapine MetabolismDay Clo D C (ng/ml) C/D Ratio
mg/day Clo NorC Total Clo Total
-168 500 653 242 895 1.3 1.8
-164 500 755 274 1029 1.5 2.1
-143 400 557 185 742 1.4 1.9
-136 400 704 204 908 1.8 2.3
-108 500 823 303 1126 1.7 2.3
-73 400 621 196 817 1.6 2.0
-45 450 613 201 814 1.4 1.8
-16 450 657 181 838 1.5 1.9
11 450 1451 484 1935 3.2 4.3
21 450 693 222 915 1.5 2.0
46 450 738 243 981 1.6 2.2
67 450 529 193 722 1.2 1.6
123 350 327 129 456 0.9 1.3
151 350 318 126 444 0.9 1.3
179 350 311 127 438 0.9 1.3
207 350 327 129 456 0.9 1.3
263 450 433 162 595 1.0 1.3
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4.4.3.4. Case 4: Longitudinal Course of Clozapine Metabolism
■ Clozapine metabolism longitudinal course:
□ slightly ↓: competitive inhibition
by multiple medications
□ very ↓: competitive inhibition
by adding perphenazine
to multiple medications
□ slightly ↓: competitive inhibition
by multiple medications
□ normal: after stopping other medications.
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Questions
■ Please review the 10 questions in the pdf
document entitled “Questions on the Presentation:
Clozapine Case 4”.
■ You will find the answers on the last slide after the
“Thank you slide”. No peeking until you have
answered all the questions.
■ If you do not answer all the questions correctly,
please review the PowerPoint presentation again
to reinforce the pharmacological concepts.
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Thank you
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Answers
1. D 6. B
2. D 7. D
3. C 8. A
4. D 9. D
5. A 10. B