TDM. Measurement techniques used to determine cyclosporine level include:

Transcription

1 TDM Lecture 15: Cyclosporine. Cyclosporine is a cyclic polypeptide medication with immunosuppressant effect. It has the ability to block the production of interleukin-2 and other cytokines by T-lymphocytes. It is mainly used for the prevention of graft rejection in transplantation procedures; it is also used for the management of other autoimmune diseases like psoriasis and rheumatoid arthritis. Therapeutic concentration: The range of desired cyclosporine concentration is usually different based on measurement technique used, type of biological sample assessed (blood, plasma or serum) and the type of medical condition being treated. Measurement techniques used to determine cyclosporine level include: - HPLC (High Pressure Liquide Chromatography): very specific for cyclosporine only (do not measure cyclosporine s metabolites). - Immunoassay technique (polyclonal antibodies): less specific because it measures both cyclosporine and its metabolites, however this technique is more rapid. Cyclosporine is bound to red blood cells and as such the measured concentration of cyclosporine in blood sample will be higher than that in serum or plasma. Since cyclosporine s metabolites are mainly excreted by bile, liver transplant patients may have high level of cyclosporine s metabolites in their blood, serum or plasma immediately after operation because the new graft (liver) has not begun functioning and not yet able to produce bile. For kidney transplant patients, cyclosporine treatment may be delayed and when used it should be administered in lower doses. This is because cyclosporine has nephrotoxic effect and its use can damage the transplanted kidney. After transplantation procedure, the new kidney has not yet begun functioning and risk of cyclosporine nephrotoxicity is enhanced. In hematopoietic stem cell transplantation patients, cyclosporine can be employed to avoid graft versus host effect. Here, donor hematopoietic stem cells are transferred to leukemia patients and the new graft will start producing normal T-lymphocytes. These new T-lymphocytes can recognize host (recipient) antigen as non-self-antigen, and this can start an immunologic reaction that can damage body tissues. 1

2 Possible adverse effects of cyclosporine include: - Hypertension. - Nephrotoxicity (usually, dose dependent). - Hyperlipidemia. - Hirsutism and gingival hyperplasia. Basic pharmacokinetic parameters: Cyclosporine follows a linear pharmacokinetics (two compartment model), it is mainly eliminated by liver (almost 99%). There is a considerable variability in day to day level of cyclosporine even when the drug had reached steady-state concentration. This variability is due to the involvement of many factors influencing oral absorption and hepatic metabolism. During cyclosporine oral absorption, a double-peak phenomenon can be observed. Here, a first serum peak (maximum concentration) can be measured 2-3 hours after administration then another peak (maximum concentration) can be recognized 2-4 hours after that. This can increase pharmacokinetics complexity of cyclosporine. For oral absorption, cyclosporine has poor water solubility and this can hinder its absorption through GIT. Newer micro-emulsion dosage forms had been developed which can provide better bioavailability and more consistent absorption. Other factors that can affect oral absorption of cyclosporine include: - Increased bowel movement can decrease absorption of cyclosporine through GIT (decreased contact time with intestinal surface). This is very common in diarrhea associated with graft versus host reaction in transplantation patient. - In liver transplantation patient, the new liver has not yet begun functioning (immediately after operation). The secretion of bile salt to GIT is very low, it had been proved that low bile level in GIT can decrease absorption of cyclosporine due to limited dissolution. - Grapefruit juice should be avoided in patients on cyclosporine therapy as this juice can inhibit P-glycoproteins in GIT and increase oral bioavailability. Regarding liver elimination, cyclosporine has low to medium hepatic extraction ratio and as such its hepatic clearance (Cl H ) is influenced by unbound fraction (f B ), intrinsic capacity of the liver (Cl int ) and liver blood flow (LBF). 2

3 The hepatic clearance of cyclosporine can be influenced as the following: - Unbound (free fraction) of cyclosporine: this drug is mainly bound to red blood cells (erythrocytes) and lipoproteins. Erythrocytes level can vary in patients with hematopoietic stem cell transplantation or those with kidney transplant. Hyperlipidemia is a possible adverse effect for cyclosporine and this can affect the free fraction of cyclosporine by changing the level of lipoproteins. - The intrinsic capacity of the liver (Cl int ) can vary in patients with liver transplants or those receiving drugs that can inhibit or induce microsomal enzymes. Grapefruit juice is a well-known inhibitor of liver enzymes and can reduce hepatic clearance of cyclosporine. Cyclosporine is available in the following dosage forms: - Cyclosporine capsule (25 mg, 50 mg and 100 mg). - Cyclosporine solution (100 mg/ 5 ml). - Cyclosporine micro-emulsion capsule (25 mg and 100 mg). - Cyclosporine micro-emulsion solution (100 mg/ 5 ml). - Cyclosporine IV solution (50 mg/ ml) to be diluted with normal saline or dextrose water and infused over 2-6 hours. Effect of diseases and conditions on cyclosporine pharmacokinetics: In liver failure patients, the clearance of cyclosporine will decrease and half-life increase due to decreased intrinsic capacity of the liver. Immediately after operation in liver transplantation patients, the clearance of cyclosporine will be diminished because the grafted liver has not begun functioning yet. Obesity doesn t have any effect on pharmacokinetics of cyclosporine and ideal body weight should always be used in calculating cyclosporine dose. Drug interaction: - Concomitant administration of nephrotoxic medications: the risk of nephrotoxicity can increase if the patient on cyclosporine is also receiving other nephrotoxic drugs like aminoglycoside antibiotics, vancomycin or NSAIDs. - The administration of hepatic enzymes inducers like phenytoin, carbamazepine or phenytoin can enhance the clearance of cyclosporine. 3

4 - The administration of hepatic enzymes inhibitors like macrolide antibiotics or antifungal agents (ketoconazole or fluconazole) can reduce hepatic clearance of cyclosporine. - Amiodarone, verapamil and grapefruit can inhibit microsomal enzymes (reduce hepatic clearance) and inhibit P-glycoproteins (increase oral bioavailability) and therefore these chemicals can increase blood level of cyclosporine. Initial dose determination of cyclosporine: - Pharmacokinetic dosing method. - Literature based recommended dosing. Pharmacokinetic dosing method: this method involves the following general steps: - Estimate clearance: As cyclosporine is eliminated by liver mainly, we will estimate clearance by using average clearance measured previously for population with similar disease states and conditions. For drugs eliminated by liver, there is no good marker for liver function that can be used to estimate clearance of liver metabolized drugs. (For drugs eliminated by kidney, we used serum creatinine and creatinine clearance to estimate the clearance of these drugs). - Select desired steady-state concentration of cyclosporine: The desired Css of cyclosporine is variable and depends on type of transplantation surgery, type of sample collected (blood, serum or plasma) and measurement (assay) technique. - Calculate cyclosporine dose: For oral dosage form, the equation used is as following: Where: D = (Css * Cl * τ)/ F D is the maintenance dose in mg. Css is the steady-state concentration in ng/ ml or µg/ L. Cl is the clearance in L/ h. τ is the dosing interval in hours. F is bioavailability factor = 0.3. For IV intermittent infusion the equation used: D = Css * Cl * τ For continuous IV infusion, the equation used is: K 0 = Css * Cl, where K 0 is the infusion rate in mg/ h. 4

5 Example 1: HO is a 50-year-old, 75-kg (5 ft 10 in) male renal transplant patient 2 days post-transplant surgery. The patient s liver function tests are normal. Suggest an initial oral cyclosporine dose designed to achieve a steady-state cyclosporine trough blood concentration equal to 250 ng/ml. 1. Estimate cyclosporine clearance: Average clearance of cyclosporine in adult patient with normal liver is 6 ml/ min/ Kg. Cl = 6 ml/ min/ Kg * 75 Kg = 450 ml/ min. Cl = 450 ml/ min * 60 min/ h / 1000 ml/ L = 27 L/ h. 2. Calculate maintenance dose of cyclosporine: D = (Css * Cl * τ)/ F D = (250 µg/ L * 27 L/ h * 12 h)/ 0.3, usually cyclosporine is given twice daily. D = µg / 1000 µg/ mg = 270 mg rounded to 300 mg given every 12 hours. Cyclosporine serum concentration must be measured on daily basis and steady-state concentration can be reached after 5 half-lives (5 * 10 h= 50 h or almost 2 days). Average half-life in adult patient with normal liver is 10 hours. Example 2: Same patient as in example 1, except compute an initial dose using intravenous cyclosporine. 1. Estimate clearance of cyclosporine: Average clearance of cyclosporine for adult patient with normal liver is 6 ml/ min/ Kg. Cl = 6 ml/ min/ Kg * 75 Kg = 450 ml/ min Cl = 450 ml/ min * 60 min/ h / 1000 ml/ L = 27 L/ h 5

6 2. Calculate maintenance dose: If cyclosporine is given as intermittent IV infusion every 12 hours then: D = Css * Cl * τ, where F value for IV solution is 1. D = 250 µg/ L * 27 L/ h * 12 h = µg D = µg/ 1000 µg/ mg = 81 mg rounded to 75 mg given every 12 hours. If cyclosporine is given as continuous IV infusion then: K 0 = Css * Cl = 250 µg/ L * 27 L/ h = 6750 µg/ h K 0 = 6750 µg/ h / 1000 µg/ mg = 6.75 mg/ h rounded to 7 mg / h. Cyclosporine serum concentration must be measured on daily basis and Css will be reached after 5 half-lives or after almost 2 days (5 * 10 h = 50 hours). Average half-life of cyclosporine in adult patient with normal liver function is 10 hours. Literature based recommended dosing: The range of values used here is originally derived from pharmacokinetic dosing method but later were modified based on clinicians experience. Generally speaking a cyclosporine dose of 8-18 mg/ Kg/ d can be used for oral dosage forms while the dose for intravenous dosage form is 1/3 that for oral dosage form (F for IV = 1 and for oral dosage form = 0.3). In other words the intravenous dose of cyclosporine is 3-6 mg/ Kg/ d. Example 1: HO is a 50-year-old, 75-kg (5 ft 10 in) male renal transplant patient 2 days post-transplant surgery. The patient s liver function tests are normal. Suggest an initial oral cyclosporine dose designed to achieve a steady-state cyclosporine trough blood concentration within the therapeutic range. The suggested oral dose of cyclosporine is 8-18 mg/ Kg/ d. Because this is a patient with a kidney transplant then we will use the lower end of the range (8 mg/ Kg/ d) to avoid nephrotoxicity. D = 8 mg/ Kg/ d * 75 Kg = 600 mg/ d given as 300 mg every 12 hours. 6

7 Cyclosporine serum concentration must be measured daily and Css can be reached after 5 half-lives or almost 2 days (5 *10 h = 50 h), the average half-life for adult patient with normal liver function is 10 hours. Example 2: Same patient as in example 3, except compute an initial dose using intravenous cyclosporine. The suggested intravenous dose of cyclosporine is 3-6 mg/ Kg/ d. Since the patient had renal transplant then we will use the lower range end (3 mg/ Kg/ d) to avoid possible nephrotoxicity. For intravenous intermittent infusion: D = 3 mg/ Kg/ d * 75 Kg = 225 mg/ d rounded to 200 mg/ d given as 100 mg every 12 h. For continuous intravenous infusion: K 0 = 3 mg/ Kg/ d * 75 Kg = 225 mg/ d / 24 h/d = 9.4 mg/ h rounded to 9 mg/ h. Cyclosporine serum concentration must be measured on daily basis; Css will be achieved after almost 2 days or 5 half-lives (5 * 10 h = 50 h). Use of cyclosporine serum concentration to alter dose: Measurement of serum level for cyclosporine to adjust daily dose is mandatory because of narrow therapeutic window, significant pharmacokinetics variability and possibility of serious adverse effects. The dose of cyclosporine can be adjusted by several methods: - Linear pharmacokinetics method. - Pharmacokinetic parameter method. - Area under the concentration-time curve method. Linear pharmacokinetics method: Since the steady-state serum concentration is directly proportional to the dose then the following equation can be employed: D new = (Css new / Css old ) * D old 7

8 Example 1: LK is a 50-year-old, 75-kg (5 ft 10 in) male renal transplant recipient who is receiving 400 mg every 12 hours of oral cyclosporine capsules. He has normal liver function. The current steady-state cyclosporine blood concentration equals 375 ng/ml. Compute a cyclosporine dose that will provide a steady-state concentration of 200 ng/ml. Current daily dose of cyclosporine = 400 mg * 2 = 800 mg/ d D new = (Css new / Css old ) * D old D new = (200 ng/ ml / 375 ng/ ml) * 800 mg/d = 427 mg/d rounded to 400 mg/d given as 200 mg every 12 hours. The steady-state blood concentration of cyclosporine can be achieved in 3-5 half-lives; in this case Css will be reached after almost 2 days (5 * 10 h = 50 h). The average t1/2 for cyclosporine in adult patient with normal liver is 10 hours. Steady-state blood concentration must be measured if adverse effects of cyclosporine are noticed or signs of transplant rejection are observed. Example 2: LK is a 50-year-old, 75-kg (5 ft 10 in) male renal transplant recipient who is 5 months post-transplant and receiving 400 mg every 12 hours of oral cyclosporine capsules. He has normal liver function. The current C2 steady-state cyclosporine blood concentration equals 1500 ng/ml. Compute a cyclosporine dose that will provide a C2 steady-state concentration of 800 ng/ml. Note: C2 steady-state blood concentration means that the concentration of cyclosporine was measured 2 hours (+/- 15 minutes) after dose administration. Current total daily dose of cyclosporine = 400 mg * 2 = 800 mg/d. D new = (Css new / Css old ) * D old D new = (800 ng/ ml / 1500 ng/ ml) * 800 mg/d = 427 mg/ d rounded to 400 mg/ d given as 200 mg every 12 hours. The steady-state blood concentration of cyclosporine can be achieved in 3-5 half-lives; the average t1/2 for cyclosporine in adult patient with normal liver is 10 hours. In this case Css will be reached after almost 2 days (5 * 10 h = 50 h). Steady-state blood 8

9 concentration must be measured if adverse effects of cyclosporine are noticed or signs of transplant rejection are observed. Example 3: FD is a 60-year-old, 85-kg (6 ft 1 in) male liver transplant patient who is receiving 75 mg every 12 hours of intravenous cyclosporine. The current steady-state cyclosporine concentration equals 215 ng/ml. Compute a cyclosporine dose that will provide a steadystate concentration of 350 ng/ml. Current total daily dose of cyclosporine = 75 mg * 2 = 150 mg/ d. D new = (Css new / Css old ) * D old D new = (350 ng/ ml / 215 ng/ ml) * 150 mg/ d = 244 mg/ d rounded to 250 mg/ d given as 125 mg every 12 hours. This would represent intermittent IV dosing. The steady-state blood concentration of cyclosporine can be achieved in 3-5 half-lives; the average t1/2 for cyclosporine in adult patient with liver transplantation is 20 hours as the new liver may not yet start functioning. In this case Css will be reached after almost 4 days (5 * 20 h = 100 h). Steady-state blood concentration must be measured if adverse effects of cyclosporine are noticed or signs of transplant rejection are observed. If cyclosporine is administered as continuous IV infusion then calculations will be as follows: Current total daily dose of cyclosporine = 150 mg/d / 24 h/d = 6.25 mg/h. D new = (Css new / Css old ) * D old D new = (350 ng/ ml / 215 ng/ ml) * 6.25 mg/ h = 10 mg/ h. Pharmacokinetic parameter method: In this method, we use current (old Css) to compute patient s unique pharmacokinetics constants like clearance and then use this clearance to compute the new dose that can yield the desired steady-state concentration. The dose of cyclosporine can be calculated by the following equation: D = (Css * Cl * τ)/ F, through rearrangement we can get the following: 9

10 Cl = [F (D/τ)]/ Css, where: - Cl is the clearance in L/ h. - F is the bioavailability factor, for IV solution =1 while for oral dosage form = D is the cyclosporine dose in mg. - τ is the dosage interval in hours. - Css is the steady-state concentration in ng/ ml or µg/ L. Example 1: LK is a 50-year-old, 75-kg (5 ft 10 in) male renal transplant recipient who is receiving 400 mg every 12 hours of oral cyclosporine capsules. He has normal liver function. The current steady-state cyclosporine blood concentration equals 375 ng/ml. Compute a cyclosporine dose that will provide a steady-state concentration of 200 ng/ml. 1. Calculate cyclosporine clearance. Cl = [F (D/τ)]/ Css Note: Css = 375 ng/ ml = 375 µg/ L = mg/ L Cl = [0.3 (400 mg/ 12 h)] / mg/ L = 26.7 L/ h. 2. Calculate the new dose. D = (Css * Cl * τ)/ F D = (200 µg/ L * 26.7 L/ h * 12 h)/ 0.3 = µg D = µg / 1000 µg/ mg = mg rounded to 200 mg given every 12 hours. The steady-state blood concentration of cyclosporine can be achieved in 3-5 half-lives; in this case Css will be reached after almost 2 days (5 * 10 h = 50 h). The average t1/2 for cyclosporine in adult patient with normal liver is 10 hours. Steady-state blood concentration must be measured if adverse effects of cyclosporine are noticed or signs of transplant rejection are observed. Example 2: FD is a 60-year-old, 85-kg (6 ft 1 in) male liver transplant patient who is receiving 75 mg every 12 hours of intravenous cyclosporine. The current steady-state cyclosporine concentration equals 215 ng/ml. Compute a cyclosporine dose that will provide a steadystate concentration of 350 ng/ml. 10

11 1. Calculate cyclosporine clearance. Cl = (D/τ)/ Css, F value was omitted as it is equal to 1. Css = 215 ng/ ml = 215 µg/ L = mg/l. Cl = (75 mg/ 12 h)/ mg/ L = 29 L/ h. 2. Calculate the new dose. D = Css * Cl * τ D = 350 µg/ L * 29 L/ h * 12 h = µg. D = µg / 1000 µg/ mg = mg rounded to 125 mg given every 12 hours (intermittent IV dosing). The steady-state blood concentration of cyclosporine can be achieved in 3-5 half-lives; the average t1/2 for cyclosporine in adult patient with liver transplantation is 20 hours as the new liver may not yet start functioning. In this case Css will be reached after almost 4 days (5 * 20 h = 100 h). Steady-state blood concentration must be measured if adverse effects of cyclosporine are noticed or signs of transplant rejection are observed. For continuous IV infusion: 1. Calculate clearance of cyclosporine: K 0 = Css * Cl K 0 = D/τ = 75 mg/ 12 h = 6.25 mg/ h Css = 215 ng/ ml = 215 µg/ L = mg/ L Cl = K 0 / Css = 6.25 mg/ h / mg/ L = 29 L/ h. 2. Compute the new dose: K 0 = Css * Cl = 350 µg/ L * 29 L/ h = µg/ h K 0 = µg/ h / 1000 µg/ mg = 10 mg/ h. 11

12 Area under the concentration-time curve method: Several studies found a strong correlation between multiple post-dose steady-state concentrations and AUC (Area Under the Curve). Using special regression equation, these 3-4 steady-state concentrations of cyclosporine can be converted into corresponding AUC as seen below: AUC 0 4h (in [μg h]/l) = C 1h + (0.9 C 2h ) + (1.4 C 3h ), for kidney transplantation. Where C 1h, C 2h, C 3h are steady-state cyclosporine concentrations in μg/l obtained 1, 2, and 3 hours, respectively, after a dose. Then the estimated AUC can be employed to adjust cyclosporine dose using linear pharmacokinetics equation. D new = (AUC new / AUC old ) * D old Example 1: GQ is a 47-year-old, 78-kg (6 ft 1 in) male who has undergone renal transplantation. He is receiving 400 mg every 12 hours of oral cyclosporine. The following cyclosporine steady-state concentrations have been measured to determine an estimated AUC 0 4h: C 1h = 412 ng/ml, C 2h = 1251 ng/ml, C 3h = 1009 ng/ml. Compute a cyclosporine dose that will provide a steady-state AUC 0 4h of 5000 (μg h)/l. 1. Estimate current AUC 0-4h. AUC 0 4h (in [μg h]/l) = C 1h + (0.9 C 2h ) + (1.4 C 3h ) AUC 0 4h = µg/ L+ (0.9 * 1251 µg/ L) + (1.4 * 1009 µg/ L) AUC 0 4h = (μg h)/l 2. Compute new dose. D new = (AUC new / AUC old ) * D old Current total daily dose of cyclosporine = 400 mg * 2 = 800 mg/d D new = (5000 (μg h)/l / (μg h)/l) * 800 mg/d D new = 1247 mg/ d rounded to 1200 mg/ d given as 600 mg every 12 hours. 12

13 Problems: Problem 1: AS is a 9-year-old, 35-kg female (4 ft 6 in) hematopoietic stem cell transplantation patient who requires therapy with oral cyclosporine. She has normal liver function. Suggest an initial cyclosporine dosage regimen designed to achieve a steady-state cyclosporine concentration equal to 250 ng/ml. Using pharmacokinetic dosing method: 1. Estimate cyclosporine clearance. The clearance rate for cyclosporine in pediatric patient is 10 ml/ min/ Kg. Cl = 10 ml/ min/ Kg * 35 Kg = 350 ml/ min. Cl = 350 ml/ min * 60 min/ h / 1000 ml/ L = 21 L/ h. 2. Compute cyclosporine dose. D = (Css * Cl * τ)/ F Css = 250 ng/ ml = 250 µg/ L. D = (250 µg/ L * 21 L/ h * 12 h)/ 0.3 = µg. D = µg/ 1000 µg/ mg = 210 mg rounded to 200 mg given every 12 h. Using literature based recommended dosing: The recommended oral cyclosporine dose is 8-18 mg/ Kg/ d. For this pediatric patient, we will use middle value of the range (12 mg/ Kg/ d). D = 12 mg/ Kg/ d * 35 Kg = 420 mg rounded to 400 mg given as 200 mg given every 12 h. Cyclosporine concentration must be measured on daily basis; the average half-life of cyclosporine in pediatric patients with normal liver is 6 hours. A steady-state concentration can be reached after 3-5 half-lives or after 30 hours of treatment (5 * 6 h = 30 hours). Css of cyclosporine must be measured if graft-versus- host disease is observed or adverse effects of cyclosporine are evident. 13

14 Problem 2: Patient AS (please see problem 1) was prescribed 150 mg every 12 hours of cyclosporine solution for 3 days, and the steady-state cyclosporine concentration equals 173 ng/ml. The patient is assessed to be compliant with her dosage regimen. Suggest an oral cyclosporine dosage regimen designed to achieve a steady-state cyclosporine concentration equal to 250 ng/ml. Using linear pharmacokinetics method: Current total daily dose of cyclosporine = 150 mg * 2 = 300 mg/ d. D new = (Css new / Css old ) * D old D new = (250 ng/ml / 173 ng/ml) * 300 mg/ d D new = 433 mg/ d rounded to 400 mg/ d given as 200 mg every 12 hours. Using pharmacokinetic parameter method: 1. Estimate clearance of cyclosporine. Cl = [F (D/τ)]/ Css Css = 173 ng/ ml = 173 µg/ L = mg/ L Cl = [0.3 (150 mg/ 12 h)]/ mg/ L = 21.6 L/ h 2. Calculate new dose. D = (Css * Cl * τ)/ F D = (250 µg/ L * 21.6 L/ h * 12 h)/ 0.3 = µg D = µg / 1000 µg/ mg = 216 mg rounded to 200 mg given every 12 hours. Cyclosporine will reach steady-state level after 3-5 half-lives. The average t1/2 in pediatric patients with normal liver is 6 hours. In this patient, cyclosporine will reach steady-state level after 30 hours (5 * 6 h = 30 h). Css of cyclosporine must be measured if signs of graft-versus-host disease are observed or adverse effects of cyclosporine toxicity are encountered. 14