Download 6 points each

NAME________________________________
SHORT ANSWERS (6 points each)
(Show calculations where appropriate, elaborate beyond space provided only if you feel necessary)
1. Olanzapine is classified as an “atypical antipsychotic” (you will learn about the meaning of that later).
Clozapine (Clozaril®) is another atypical antipsychotic agent. Compare the official labeling for clozapine
and olanzapine and discuss some factors that you might consider to choose one drug over the other. Which
drug appears to be the most potent? Would potency be a factor in your choice?
Olanzapine appears to be the most potent. The usual adult dose is 5-15 mg PO QD, whereas the
usual adult dose for clozapine is 150-300 mg PO BID. Taken at face values olanzapine appears to
be 300/5 = 60 times more potent.
Potency would not be the most important factor. Clozapine comes with a serious warning of
agranulocytosis. “Warning significant risk of agranulocytosis – should be reserved for use in the
treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate
courses of standard antipsychotic drug. This warning does not appear in ePocrates, probably for a
lack of space. Clozapine does not even appear among the drugs listed on the PDA version of the
Physician’s Drug Handbook.
2. Olanzapine has a pKa of 7.37 (make it 7.4). What is the percentage of olanzapine that will be ionized and
non-ionized in the stomach (assume pH = 2.4, gut (assume pH = 6.4) and blood plasma (assume pH = 7.4),
respectively? Does this information shed any light on any of the other features of olanzapine that were
provided from the official labeling?
Olanzapine would be APPROXIMATELY:
50% ionized in the plasma at pH 7.4
90% ionized in the gut at pH 6.4
99.999% ionized in the stomach at pH 2.4
The fact that the time to peak plasma concentration is 6 hours suggests that olanzapine is not
absorbed significantly from the stomach, but more from the gut. This might be predicted from its high
degree of ionization in the stomach compared to the gut.
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NAME________________________________
SHORT ANSWERS (6 points each)
(Show calculations where appropriate, elaborate beyond space provided only if you feel necessary)
3. In basic chemical experiments, while olanzapine was being developed, technicians found it to be practically
insoluble in water. The technician dialyzed a dilute suspension of olanzapine in water at pH 7.4 across a
semi-permeable membrane, with human plasma, also at pH 7.4, on the other side of the membrane.
Overnight, the insoluble particles disappeared from the water. What happened? (Hint: a drawing may help).
A very small amount is soluble in water; half would be ionized at pH 7.4, half would be unionized and
more likely to permeate the membrane. Once a molecule permeated the membrane, it would be
bound to plasma proteins (which remain concentrated on one side of the membrane because they are
too big to permeate the membrane). Overnight, this would have the effect of “sucking” most of the
olanzapine from the water side to the plasma side of the membrane.
4. There is evidence that antagonism of dopamine D2 receptors is critical for the mechanism of action of
antipsychotic compounds. Haloperidol is a “typical” antipsychotic that has been used for a number of years.
Haloperidol has affinity for dopamine D2 receptors that is about 10 times higher than the affinity of
olanzapine. What are several possible reasons why the typical human dose and dosing schedule of
olanzapine (10 mg once daily) for the treatment of schizophrenia is not simply 10 times higher than the
average human dose and dosing schedule of haloperidol for the treatment of schizophrenia (2 or 3 mg BID
or TID)?
Several factors could account for the dose of olanzapine not simply being 10 times higher than
haloperidol; a drug that binds 10 times more tightly to the D2 receptors. These include different:
bioavailability
volume of distribution
half-life
From the multiple daily dosing of haloperidol it is reasonable to guess that it has a shorter half life
than olanzapine. This is confirmed by checking resources such as Goodman & Gilman:
Olanzapine = 30 h average half life
Haloperidol = 18 h average half life
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NAME________________________________
SHORT ANSWERS (6 points each)
(Show calculations where appropriate, elaborate beyond space provided only if you feel necessary)
5. Assuming mean values for pharmacokinetic parameters, what is the predicted steady state concentration of
olanzapine in a human patient with a body mass of 70 kg given 10 mg of olanzapine per day?
A bioavalability of 0.6 for olanzapine was inferred from the statement that about 40% of the drug was
metabolized during the first pass. The clearance was stated to be 25L/h. It is reasonable to infer that
such values apply to a ‘standard 70 kg person’. Thus:
Css = ((10 mg/24h) * 0.6)/(25 L/h) = 0.0104 mg/L
PS; Your mileage will vary depending on the bioavailability that you assumed (forgetting to include
bioavailability in your calculation is not acceptable) and on what value you assumed for the clearance.
6. In the same patient as above, assume that 20 mg/day were given. What is the predicted steady state
concentration? What sentence in the labeling justifies your underlying assumption for this estimate?
The predicted value is 0.0208 mg/L. This is a doubling of predicted Css based on a doubling of the
dosing rate. It is important to note that: “olanzapine displays linear kinetics over the clinical dosing
range”.
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NAME________________________________
SHORT ANSWERS (6 points each)
(Show calculations where appropriate, elaborate beyond space provided only if you feel necessary)
7. What is the most probable reason that the elimination of olanzapine is faster in smokers than nonsmokers?
This is probably due to the induction of CYP1A2 by the aromatic hydrocarbons in smoke. Smoking is
known to induce 1A2 which appears to be a major metabolic pathway for olanzapine. Although 2D6
may metabolize olanzapine, as noted in question #18, it is a minor pathway.
8. Some drugs are rapidly removed from patients who are on chronic renal dialysis. What is the most probable
reason that olanzapine is not very effectively removed by dialysis?
Probably because of the large volume of distribution – most of the drug is not in the plasma which is
dialyzed. Furthermore, drug which is present in the plasma is almost all bound to plasma proteins.
Thus, the fraction of the total drug in the body that is ‘freely diffusible’ across a dialysis membrane at
any given time is very small.
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NAME________________________________
SHORT ANSWERS (6 points each)
(Show calculations where appropriate, elaborate beyond space provided only if you feel necessary)
9. Dry mouth is a major side effect of olanzapine in many patients. Orthostatic hypotension is also seen in
some patients. Theoretically, what kinds of change(s) in receptor binding would be desirable in a new drug
(call it “neo-olanzapine”) that would have the same therapeutic effect and potency as olanzapine, but less
dry mouth. How could the development of such a compound be pursued most effectively? Similarly, how
might one reduce the incidence of orthostatic hypotension?
“Olanzapine’s antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects.”
Anticholinergic effects cause dry mouth among other symptoms. Thus, relatively decreased affinity
for M1-5 receptors may decrease dry mouth. The dry mouth is probably caused by blockade of
peripheral M3 receptors in the salivary glands (Ki value similar to those for serotonin and dopamine
receptors; the presumed ‘therapeutic receptors’).
Orthostatic hypotension is probably related to blockade of vascular α1 adrenergic receptors (Ki =19
nM, similar to Ki values for serotonin and dopamine receptors. Developing a drug with relatively less
affinity for α1 adrenergic receptors would probably reduce the side effect of orthostatic hypotension
10. If “neo-olanzapine” (above) were developed in the laboratory, what steps would be required to establish
safety and clinical efficacy of neo-olanzapine in humans? Assuming that neo-olanzapine is subsequently
approved for short-term treatment of schizophrenia, could it be prescribed for any other conditions?
Phase I: Administration to normal volunteers for dose finding, preliminary pharmacokinetic studies
and identification of minor toxicity.
Phase II: Administration to a limited number of carefully selected patients with a target disease (such
as schizophrenia) to establish possible efficacy, expand experience with the drug in humans, further
pharmacokinetics might be done. Side effects to be monitored closely. This phase may be single
blind or unblinded.
Phase III: Administration to a relatively large number of patients with the target indication (such as
schizophrenia). Often carried out in multiple centers, involves usually thousands of patients. Careful
documentation of all patients treated, therapeutic and possible adverse effects. Almost always
carried out in a randomized-controlled (placebo and/or other standard medication), double blind
manner. Unless RCT efficacy can not be assumed to have been established.
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Once approved for schizophrenia, for example, neo-olanzapine could be prescribed for other
conditions (off label). In either case, the prescriber takes on the role of the “learned intermediary”
between the manufacturer and the patient.
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NAME________________________________
SHORT ANSWERS (6 points each)
(Show calculations where appropriate, elaborate beyond space provided only if you feel necessary)
11. Weitoo Lowe is a 267 pound patient who lived alone. He had been provided a number of prescriptions
for olanzapine over the course of about a year. Recently, he was found dead at age 32 in his home one
day after a family reunion at which he appeared normal. The prescription bottles were not located. An
autopsy provided no structural explanation of Mr. Lowe’s death. The toxicology report indicated a
serum olanzapine concentration of 1238 ng/mL. What was the apparent total amount of olanzapine in
his body at the time of Mr. Lowe’s death, assuming no post-mortem redistribution? What is your
opinion regarding the cause of death?
Mr. Lowe’s body mass is 121.4 kg (267 pounds/2.2 pounds/kg).
If it is assumed that a Vd of approximately 1000L applies to a 70 kg person, then the Vd in Mr. Lowe
would be predicted to be 1740 L (1000 L * 121.4 kg/70 kg). The total amount of drug in the body
thus appears to be:
1.238 mg/L * 1740 L = ~2154 mg.
This represents a high amount. The cause of death was probably due to toxic effects of olanzapine.
The PDR states that accidental ingestion of 300 mg of olanzapine in one patient was associated with
drowsiness and slurred speech. Mr. Lowe’s death was probably due to an accidental or, more likely,
suicidal, ingestion rather than accumulation during chronic medical treatment. He would almost
certainly have shown signs of accumulating the drug on the day prior to his death in the latter case.
Suicide is, of course not uncommon among depressed patients (maybe especially after the reunion of
a dysfunctional family?) and one always needs to be aware of the potential.
PS: Don’t be misled by the data in the next question. Mr. Lowe may represent a rather susceptible
human – and besides there are substantial difference in toxicity between species. The median
therapeutic index is only a rough guide.
12. Assume that the LD50 for olanzapine is 50 mg/kg in mice. What else would you need to know to estimate
the median therapeutic index of olanzapine in mice? How might one measure that? Assume that you have
done such measurements, and that the value in question (what is it called?) was 0.25 mg/kg. If so, what is
the apparent median “therapeutic index” for mice?
One would need some definition of a “therapeutic effect” in mice. Probably some behavioral test with
a quantal response would be conducted to determine the median effective dose (ED50). If the ED50
were 0.25 mg/kg, then the apparent median therapeutic index in mice would be:
55 mg/kg/0.25 mg/kg = 220
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NAME________________________________
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NAME________________________________
SHORT ANSWERS (3 points each)
(Show calculations where appropriate, elaborate beyond space provided only if you feel necessary)
Assuming that the respective Ki values for olanzapine at various receptors are equal to the respective
Kds:
13. What would be the predicted approximate pA2 value of olanzapine versus dopamine at the dopamine D1
receptor?
If the Ki of 11 nM is assumed to represent the Kd of olanzapine from D1, then:
Kd = 11 nM = 1.1 x 10–8 M; pA2 thus ~ 8
14. Approximately how much more (or less) tightly does olanzapine bind at the 5HT2C than the dopamine D1
receptor?
The Ki for 5HT2c is 11 nM. If that is equal to the Kd, then olanzapine shows the same apparent
affinity for the 5HT2c and D1 receptors .
15. Approximately how much more (or less) tightly does olanzapine bind at the H1 receptors than α adrenergic
receptors?
Olanzapine binds about 3 times more tightly to the H1 than the alpha1-adrenergic receptor (7 nM
compared to > 19 nM).
16. Administration of olanzapine once daily leads to steady-state concentrations “in about one week.” Is this
what you would expect?
If one uses the rule of thumb of 5 half-lives for attainment of steady state and assumes an average
half-life of 30 hours, then it would require 6.25 days (5 x 30 hours) – about a week.
HuBio 543
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NAME________________________________
SHORT ANSWERS (2 points each)
(Show calculations where appropriate, elaborate beyond space provided only if you feel necessary)
17. Is olanzapine metabolized by phase I or by phase II drug metabolic reactions?
Both. Direct glucuronidation is a phase II reaction without a phase I reaction. And, of course, the
“CYP mediated oxidation” is a phase I reaction.
18. Olanzapine clearance is not reduced in subjects who are deficient in CYP2D6 (lucky for the Eli Lilly Co.)
Approximately what % of the population is deficient in this enzyme and how were such individuals
identified in the days before mRNA arrays?
About 3-10% of the Caucasian population are affected by 2D6 deficiency. These were originally
identified as slow metabolizers of debrisoquin.
19. A small fraction of olanzapine is excreted in the urine unchanged. What are the most likely reasons that
this fraction is so small?
Olanzapine is highly bound to plasma proteins. Thus a small fraction of the drug will be filtered
through glomeruli on any given pass through the liver. It is also true that olanzapine is not actively
secreted.
HuBio 543
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NAME________________________________
SHORT ANSWERS (2 points each)
(Show calculations where appropriate, elaborate beyond space provided only if you feel necessary)
20. Next to the listing for Zyprexa® in the PDR is the symbol Rx. What does that mean?
It means that Zyprexa® may be dispensed only with a valid prescription. It is not available OTC.
21. What is the Use-in-Pregnancy category of olanzapine? What does the category mean?
C. Risk cannot be ruled out.
22. What is the DEA classification of olanzapine?
None. Olanzapine is not a controlled substance.
23. What are the approved indications for treatment with olanzapine?
Schizophrenia (some sources list this as psychosis) and short term episodes of acute manic episodes
associated with bipolar I disorder. It is implied that treatment should be short term, but that a
physician who elects to use the drug for extended periods may be considered to be using the drug ‘off
label’.
24. What is the approximate bioavailability of olanzapine?
None of my sources listed a specific value. I inferred a bioavailability of 0.6 based on the statement
that “…approximately 40% of the dose [is] metabolized before reaching the systemic circulation.” You
could have inferred different numbers based on following radioactive (drug and/or metabolites – but
therein lies some vagueness)
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