1. Clinical Pharmacokinetics of Lithium and Therapeutic Drug Monitoring Michael Dolton, B.Pharm (Hons)
At the completion of this lecture you will
understand the importance of monitoring lithium concentrations due to variability in pharmacokinetics and narrow safety margin
appreciate the importance of lithium drug interactions
understand the PK-PD rationale for TDM and dose adjustment

2. Lithium First discovered in 1817 Indications
Acute treatment and prevention of mania in bipolar disorder
Augmentation for treatment-resistant depression
Available as 250mg (Lithicarb) and 450mg SR (Quilonum SR) tablets
*First used medically in 1858
*Used for psychiatric illnesses since the 1970’s.
*Also used in the treatment of chronic schizophrenia
*Quilonum tablet is controlled release

3. Lithium in Bipolar disorder
1st line therapy in acute mania and prophylaxis in bipolar disorder
Some second generation antipsychotics and anticonvulsants are also considered 1st line for these indications
Don’t stop Lithium abruptly or treat intermittently unless toxicity present
*A number of second generation antipsychotics and anticonvulsants are useful in the treatment of acute mania
*For prophylaxis in bipolar disorder, only lithium, olanzapine and lamotrigine have good evidence for preventing mania and depression
*Lamotrigine also has good evidence in the prophylaxis of mania and depression episodes in bipolar, with Lithium seemingly better at preventing mania than depression and lamotrigine better at preventing depression than mania
*Stopping Lithium abruptly has been associated with a high rate of relapse for manic episodes, and treating intermittently with lithium may worsen bipolar

4. Lithium Case History
Ms Ursla Down, 58 year exam supervisor, has been taking lithium for bipolar disorder. Her serum levels have ranged from 0.5 to 0.8 mM.
After developing peripheral oedema and is treated with hydrochlorothiazide 100 mg mane.
One week later Ursla is admitted to hospital with delirium and her serum lithium level was measured at 2.5 mM.

5. Basic Concepts Pharmacokinetics Pharmacodynamics
Drug Dose
Concentration in plasma
Concentration at effect site
Pharmacological effect
PHARMACOKINETICS
PHARMACODYNAMICS
Pharmacokinetics
what the body does to the drug
Pharmacodynamics
what the drug does to the body

6. Lithium Pharmacokinetics
J Clin Pharmacol 1994;34:

7. Renal Excretion
Renal Clearance (CLR) = filtration + secretion - reabsorption
Filtration
*Only unbound drug is filtered at the glomerulus, but since Lithium is not bound to plasma proteins, this represents all systemic lithium

8. Lithium Renal Excretion
Excreted in a similar way to sodium
Lithium CL = 26 mL/min
GFR = 120 mL/min
CLR < GFR
indicates both filtration and reabsorption
Not secreted
Lithium CL = filtration - reabsorption

9. Lithium unwanted effects
Antagonises antidiuretic hormone in kidney producing diuresis
impairs thyroid function
cause weight gain
hand tremor
inverted T-wave of ECG
*Weight gain possibly due to increased appetite, which can contribute to poor compliance

10. Lithium Toxicity Grade Manifestations
I tremor, nausea, vomiting, sedation, ataxia
II impaired consciousness, tremor, twitching
III semi-coma, convulsions
sequelae - renal impairment, cerebral damage

11. Lithium Toxicity - conc vs effect
Therapeutic mM
prophylaxis – 1.0
treatment
Toxicity
Grade I
Grade II
Grade III > 3.5
12 h post dose sample AMH 2010
*Therapeutic guidelines targets are slightly different

12. Lithium Toxicity - Treatment
Sufficient IV fluid replacement to ensure diuresis
Haemodialysis increases lithium clearance
Indicated if GFR < 60mL/min, lithium > 2.5, delirium, seizures, coma, persistent clinical effects in spite of fluids
If patient has diabetes insipidus (which many people taking lithium develop), they will have larger than normal fluid requirements due to polyuria

13. Lithium Post-distribution sample
Flat concentration-time profile
after 12 h after the conventional
or sustained release dose forms
Lithium concentration (mmol/L)
Recommended to be taken 12 hours after the PM dose of Lithium, just before the morning dose
tablet 24 12
Time (h)

14. Lithium – When to monitor
When staring lithium (once SS achieved)
Prophylaxis: Every 3-6 months
Dose changes, interacting medications started / ceased
Clinical signs of toxicity, or of lack of efficacy
Dehydration, or changes in salt intake
*1st point – may also need other medicines initially as patient can take up to 2 weeks to respond
*First level can be taken 5-7 days after starting lithium
*Also monitor kidney and thyroid function when starting lithium and every 3-6 months

15. Clinical status
The clinical status of the patient can increase the risk of toxicity such as
renal impairment or dysfunction
dehydration related to fever, vomiting, diarrhoea, heavy sweating and low salt diet

16. Drug interactions with lithium
Decreases Lithium clearance
Diuretics - sodium depleting (e.g. thiazide)
NSAID -renal PG effects
ACE inhibitors, A2RA’s
Pharmacodynamic interactions
effects with no change in lithium concentration
anticonvulsants, SSRIs, calcium channel blockers

17. Lithium vs. Sodium
80% of the filtered load of lithium is reabsorbed in tandem with sodium
Part of Nephron
Lithium
Sodium
Proximal Tubule ✓
Distal Tubule ✗
Loop of Henle
Collecting Tubules

18. Lithium + Thiazide diuretics
Thiazide diuretics decrease sodium reabsorption in the distal tubule
This creates a relative sodium deficit
Leads to a compensatory increase in proximal tubule sodium and lithium reabsorption ( Lithium in blood)

19. Lithium Case History II
Lithium and the diuretic were both withdrawn.
36 h later Ms Down experiences a manic episode and lithium at the previous dose is restarted.
Oedema was found to be related to lithium concentrations and safely treated with amiloride.

20. Lithium TDM Confused and anorexic Lithium conc (mM) 1.2 mM 0.4 mM
Manic episode
weeks
Lithium dosing
diuretic

21. Clinical Pharmacology
The Right drug
The Right patient
The Right dose
The Right time
The Right Response
The
Right
dose

22. Do we need to measure drug concentration?
For example
INR or PT for warfarin
serum cholesterol concentration measurements for pravastatin
serum urate concentration for allopurinol
blood pressure for metoprolol

23. Why measure blood levels?
Drug Dose
Concentration in plasma
Concentration at effect site
Pharmacological effect
Analytical
method
Hard to
measure
(invasive)
Hard to
measure
(outcome)
Surrogate
marker

24. What is Therapeutic Drug Monitoring?
using drug concentration data as a "surrogate" of drug effect to individualise drug therapy to ensure maximum beneficial effects with minimal adverse effects.

25. When is TDM appropriate?
pharmacological response is difficult to quantify
e.g. cyclosporin -
outcome has serious consequences
concentrations used as a surrogate indicator/predictor of outcome

26. When is TDM appropriate?
drugs used as prophylactic agents (endpoint is the absence of an event)
e.g. anticonvulsants, antiarrythmics, lithium
drugs with a narrow therapeutic range (individualise therapy to maximise benefits and minimise risks)
e.g. digoxin, anticonvulsants, cardiac antiarrhythmics, immunosuppressants

27. When is TDM appropriate?
drug clearance changes rapidly
e.g. declining renal function, change in renal function post-transplant, examining drug interactions
Monitor patient compliance
e.g suspected poor compliance, particularly for prophylactic medicine, used in clinical trials

28. When is TDM appropriate?
investigate unexpected or unexplained effects
diagnose adverse effects to define patient management especially where the adverse effects mimic the disease state e.g. cardiac arrhythmias and digoxin

29. When is TDM appropriate?
Management of overdose
urine drug screen - identify potential causes of coma
assign cause and decide management
e.g. paracetamol - decision on administration of antidote
warfarin overdose and unexplained INR

30. Commonly monitored drugs
Antibiotics
Aminoglycosides, Vancomycin
Antifungals
Flucytosine, Itraconazole, Voriconazole, Posaconazole
Anticonvulsants
Phenytoin, Carbamazepine, sodium valproate
Immunosuppressants
Cyclosporin, Tacrolimus, Sirolimus
Antiarrhythmics
Digoxin, perhexiline
Others - Theophylline

31. What is a therapeutic range?
An optimal concentration range for a DRUG is NOT the same as a "normal" range defined for biochemical parameters
Encompasses those recorded in patients experiencing therapeutic benefit and minimal toxicity

32. Concentration-effect relationship
SAFETY MARGIN
Effect
Probability
Toxicity
Drug Concentration

33. What is a therapeutic range?
optimal range has not been defined for many drugs
optimal range should only be used as a guide and should always be interpreted with the clinical assessment of the patient

34. Cyclosporin Target range?
First 3 months maintenance
Kidney : ng/ml
Liver : ng/ml
Heart : ng/ml
Heart-lung: ng/ml
BMT : ng/ml

35. Interpreting Drug level data
accurate dose history including dose (with an assessment of compliance) and duration of therapy
time of dose administration and blood sample withdrawal
patient status including age, weight and organ function (e.g. renal function assessed using estimated creatinine clearance)

36. Interpreting Drug level data
biological fluid sampled (e.g. whole blood, plasma or serum)
clinical status of patient (e.g. experiencing adverse effects)
medication history (including drugs that may potentially interact with the drug of interest)
What is the therapeutic range for THIS patient?

37. TDM vs. TCI Therapeutic Drug Monitoring (TDM)
Target Concentration Intervention (TCI)
(Holford, 1996)

38. Target Concentration Intervention (Holford and Tett)
Select target
concentration
Use population
PK and PD data
Estimate
dose
Refine estimates
on outcome
Measure a
blood level

39. Dose prediction methods
Empirical dose protocol
Nomogram using patient covariates
Bayesian Dose prediction
population pharmacokinetic approach

40. Example Nomogram - Tobramycin
Massie et al, 2006

41. Dose prediction methods
Bayesian Dose prediction
uses prior knowledge of the population pharmacokinetic parameters
information about the patient
predict PK parameters
individualize the dose
computer aided
relies on knowledge of population pharmacokinetics

42. Bayesian software - TCIWorks

43. TCIWorks – Dose prediction

44. Role of the pharmacist in TDM
Interpret relevant information
Treat the patient not the number
Use pharmacokinetic knowledge to make rational dose recommendations

45. Questions?