Clinical Pharmacokinetics of Immunosuppressants & Antivirals PDF

Clinical Pharmacokinetics: IMMUNOSUPPRESSANTS & ANTIVIRALS INTRODUCTION Drugs that suppress or prevent activity of the immune system e.g. cyclosporin, tacrolimus, azathioprines, corticosteroids. Indications: -prevent graft rejection in solid organ transplant -prevent graft vs. host dise...

Clinical Pharmacokinetics: IMMUNOSUPPRESSANTS & ANTIVIRALS INTRODUCTION Drugs that suppress or prevent activity of the immune system e.g. cyclosporin, tacrolimus, azathioprines, corticosteroids. Indications: -prevent graft rejection in solid organ transplant -prevent graft vs. host disease in bone marrow transplant -treatment of autoimmune disease e.g. psoriasis, rheumatoid arthritis, Crohn’s disease Drug monitoring is widely performed for cyclosporin & tacrolimus due to their narrow therapeutic index & substantial variability of blood concentrations CYCLOSPORIN A potent immunosuppressant, non-myelotoxic but markedly nephrotoxic. Mainly used for the prevention or treatment of graft rejection in bone marrow, kidney, liver & heart transplant. Desired cyclosporin concentrations varies depending on: -types of organ transplants -change with time during the post-transplantation phase -protocols specific to the transplantation service Goal of therapy is to prevent graft rejection in solid organ transplant or graft vs. host disease in bone marrow transplant while minimizing drug side-effects SANDIMMUNE® vs NEORAL® Sandimmune® – formulated in oily solution + excipients (corn oil, polyethoxylated castor oil, ethanol) Erratic oral absorption → poor correlation between trough level concentration & AUC → difficulty in dosing patients Neoral®– reformulated microemulsion Closer correlation between trough level concentration & AUC PHARMACOKINETIC PARAMETERS Follows linear PK → Css changes proportionately with dose Bioavailability – A highly lipid-soluble compound. Oral bioavailability varies with average of 30%. – To enhance solubility, oral cyclosporin solution is prepared with olive oil or alcohol – Oral absorption is influenced by fat content of meals Vd - Average  4-5 L/kg PHARMACOKINETIC PARAMETERS Excretion – Hepatic metabolism > 99% mainly in the CYP3A4 enzyme system – < 1% excreted unchanged in the urine. – > 25 cyclosporin metabolites eliminated in the bile – whole blood clearance  5 to 10 ml/min/kg in adult t1/2 – 6-12 hours – Varies depending on the Vd and Cl FACTORS THAT INFLUENCE PHARMACOKINETIC Age → children display  clearance (10 ml/min/kg) and shorter t1/2 (average 6hrs) for children < 16 yrs old Liver function → patients with liver failure have  clearance (3 ml/min/kg) & prolonged t1/2 (20hrs). Drug or food interactions ❖inhibition of CYP3A4 →  metabolism →  plasma cyclosporin concentration e.g. Ca channel blockers, macrolide antibiotics, azole antifugals, allopurinol, cimetidine, grapefruit juice ❖induction of CYP3A4 → metabolism →  plasma cyclosporin concentration e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort DOSE & ADMINISTRATION Oral form Capsules (25,50,100 mg) or Microemulsion solution (25,50,100 mg/ml) to be mixed with juice or milk Intravenous Oily injection 50 mg/ml to be diluted in 20–100 ml Normal Saline or 5% dextrose infused over 2–6hrs. Risk of anaphylactic reactions due to castor oil as excipient Initial dose usually started 4-12 hrs before transplant NEORAL® Soft Gelatin Capsules NEORAL® Oral Solution Sandimmune® Soft Gelatin Capsules Sandimmune® Oral Solution Sandimmune® Injection DOSE & ADMINISTRATION Solid organ transplantation – Treatment should be initiated within 12 h before surgery – 10 to 15 mg/kg given in 2 divided doses maintained as the daily dose for 1 to 2 weeks post-operatively, – Gradually reduce the dose in accordance with blood levels according to local immunosuppressive protocols until a recommended maintenance dose of about 2 to 6 mg/kg given in 2 divided doses is reached. DOSE & ADMINISTRATION Bone marrow transplantation – The initial dose should be given on the day before transplantation. – Sandimmun concentrate for solution for infusion is preferred for this purpose. – The recommended IV dose : 3–5 mg/kg/day. – Continue infusion at this dose level during the immediate post-transplant period of up to 2 weeks, before a change is made to oral maintenance therapy with Neoral at daily doses of about 12.5 mg/kg given in 2 divided doses. – Maintenance treatment should be continued for at least 3 months (and preferably for 6 months) before the dose is gradually decreased to zero by 1 year after transplant.  THERAPEUTIC RANGE Therapeutic range varies according to the type of assays & the biological fluids that have been sampled. Assay Serum/Plasma Whole blood (g/L or (g/L or ng/ml ng/ml) Monoclonal radio 50-125 150-400 immunoassay Fluorescence polarization immunoassay Polyclonal 150-400 200-800 Monoclonal 50-125 150-400 HPLC 50-125 150-400 Using whole blood, the commonly accepted level is 150-400 ng/ml or g/L. Monitoring of cyclosporin concentrations – trough/C2/AUC CYCLOSPORIN MONITORING Area Under the Concentration-Time Curve (AUC) C2 C trough  AUC MONITORING The area under the blood CsA concentration versus time curve (AUC) attained by drawing serial blood samples across this dosing interval (AUC0-12) provides the best index of CsA exposure The greatest variability occurred in the absorption phase in the initial 4–6hr after the CsA dose AUC0-12 – More accurate indication of exposure of the body to the drug In renal transplant patients → closely related to the clinical outcome Serial blood sampling → practical difficulties C2 MONITORING One clinical monitoring option proposed was to quantify this variable AUC0-4 period. This was achieved by drawing 2–3 accurately-timed blood samples in this period after the CsA dose, and then applying algorithms derived from the relevant transplant population to estimate the AUC0-4 Absorption profiling → adjusting the drug dose by targeting the blood cyclosporin concentration in the first 4 hrs after dosing C2 blood concentration at 2hrs after dose → Alternative single sample that correlates well with AUC0-4 C2 vs C0 →  rejection rates;  incidence & severity of adverse reactions 15 min “window of opportunity” MONITORING PARAMETERS Signs & Sx of graft-versus host disease- rash, diarrhoea, abdominal pain, hyperbilirubinemia,  LFT For solid organ transplant monitor for rejection consistent with transplantation Renal transplant – graft tenderness, Serum Cr, weight gain, fever, malaise, hypertension, proteinuria,  BUN (chronic rejection) Liver transplant – fever, lethargy, graft tenderness,  WCC,  LFT, jaundice (chronic) Heart transplant – low grade fever, malaise, heart failure (presence of S3 heart sound or artrial arrhythmia)  Left ventricular function, MI, coronary artery sclerosis (chronic) MONITORING PARAMETERS Adverse effects of cyclosporine → hypertension, nephrotoxicity, hyperlipidemia, tremor, hirsutism, gingival hyperplasia (common) GIT s/e, headache, hepatoxicity, hyperglycemia, hyperK (less frequent) Cyclosporin concentration C0 /C2 monitoring for dose adjustment DETERMINATION OF INITIAL DOSE For oral therapy, to compute the average cyclosporin steady state serum concentration (CSS) or maintenance dose: CSS = [F(D/]/Cl or D= (CSS * Cl * )/F where F=bioavailability fraction D=dose of cyclosporin in mg Cl=cyclosporin clearance in L/hr  = dosing interval in hours For IV route: CSS= (D/)/Cl or D= CSS * Cl *  DOSE ADJUSTMENT Cyclosporin follows linear, dose-proportional pharmacokonetics where steady state concentrations change in proportion to dose Dnew/ CSS new = Dold/ CSS old Dnew = (CSS new / CSS old )* Dold Dnew = dose required to produce the desired steady state concentration Dold = dose that produced the steady state concentration that the patient is receiving  Case 1 SK is a 50 year old, 70 kg, 170 cm male renal transplant patient 2 days post transplant surgery. His liver function test is normal. Suggest an initial oral cyclosporine dose in order to achieve a steady state cyclosporin trough concentration of 200 ng/ml. Assume that cyclosporin Cl is 6 ml/min/kg. SOLUTION 1. Estimate clearance Cl = 6ml/min/kg x 70 kg x [60 min/h / 1000 ml/L] = 25.2 L/h 2. Compute dosage regimen 12 hr dosage interval is used ng/ml = g/L so no conversion is required A conversion constant of 1000g/mg is used to change the dose to mg D = (CSS x Cl x )/F = (200 g/L x 25.2 L/h x 12h) /(0.3 x 1000 g/mg) = 201.6 mg, rounded to 200 mg every 12 h Steady state expected to occur in about 2 days assuming t1/2 = 10 h (5 half-lives = 5 x 10 h =50 h or ~2 days) CASE 2 HM is a 57 years old, 75 kg, height 165 cm male renal transplant recipient who receives 400 mg of oral cyclosporine capsules every 12 hours. He has normal liver function. The current steady state cyclosporine blood concentration is 350 ng/ml. Calculate a dose that will provide a steady state concentration of 250 ng/ml.  SOLUTION 1. Compute a new dose to achieve the desired concentration Total daily dose = 400 mg/dose x 2 doses/day =800 mg/d Dnew = (CSS new / CSS old ) x Dold = [(250 ng/ml)/(350 ng/ml)] x 800 mg/d = 571.4 mg/day, rounded to 600 mg/day Thus the new suggested dose is 600 mg/day or 300 mg every 12 hours, to be started at the next scheduled dosing time. Antiviral therapy Vaccines Can prevent viral diseases Antiviral drugs Can stop infections once started Needs to be quick Not that many in the market (relative to antibiotics) Largely limited to influenza, HIV, HBV, HCV Antivirals in used clinically Not included: antivirals in SARS-CoV-2 infection Classification of antiviral agents Anti-Herpes virus drugs – acyclovir, cidofovir, foscarnet, and valacyclovir Anti-Retrovirus drugs Anti-Influenza virus drugs – Peramivir, zanamivir, oseltamivir Nonselective Antiviral drugs Acyclovir ▪ active against most species in the herpesvirus family in the following order1 HSV-1, HSV-2, Varicella zoster virus, Epstein-Barr virus, Cytomegalovirus (CMV) – least activity ▪ F ~ 10–20% (oral), unaffected by food ▪ Protein binding 9–33% ▪ Elimination half-life 2.5–3.3 hours ▪ Excretion Kidney (62–90% as unchanged drug) Wagstaff, AJ; Drugs. 47 (1): 153–205. Acyclovir Dosing Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days. Genital Herpes: Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for 10 days. Oseltamivir ▪ An ethyl ester prodrug (oseltamivir carboxylate) ▪ Absorption ▪ F ~ 80% of oseltamivir carboxylate ▪ Active metabolite detectable from 30mins, peaks at 3-4h ▪ Food – no sig effect on Cmax and AUC ▪ Metabolism ▪ Hepatic – converted to oseltamivir carboxylate ▪ CES 1 polymorphism impairs Oseltamivir Bioactivation in Humans* ▪ Does not interact with P450 or glucuronosyltransferases Oseltamivir ▪ Distribution ▪ V = 23-26L (active metabolite) ▪ Protein binding 42% (parent drug), 3% (active metabolite) ▪ Elimination ▪ 1–3 hours, 6–10 hours (active metabolite) ▪ Urine (>90% as oseltamivir carboxylate), faeces Factors influencing PK – renal (increase Cmax, AUC), Apparent CL decreases linearly with increasing age (up to 12 years). > 12 years similar to adult patients. Targets for intervention :HIV replication  Suspected drug-drug or drug-food interactions TDM ART is not resulting in clinically altered efficacy or toxicity routinely Pathophysiologic changes that may alter a recommended, drug's pharmacokinetics, i.e. hepatic or renal dysfunction but may be useful in the Special populations, including children, elderly and pregnant women following situations: Treatment-experienced patients who may have viral isolates with reduced susceptibility Concentration-dependent toxicities Suboptimal virological response in patients with good adherence  Target ARV TDM Feasible? Rationale/Comments concentrations NRTI Possible, but may - Plasma concentrations do not correlate with Lack of not be clinically efficacy/toxicity supportive relevant - Intracellular metabolism to active derivative studies - Some studies reported an association between plasma concentrations & renal toxicities NNRTI Yes - Established relationship between drug Ctrough (mg/L) concentration & efficacies/toxicities of NNRTI, Nevirapine – 3 especially first generation (NVP/EFV) Efavirenz - 1 - Plasma conc of EFV: predictive of virological failure & adverse effects - Limited studies on 2nd gen NNRTI between plasma conc & efficacy: target concentrations for etravirine & rilpivirine not established ARV​ TDM Feasible?​ Rationale/Comments Target concentration ​ PI Yes Clear relationship between plasma conc & virological Ctrough (mg/L) (strong responses or toxicities: Atazanavir – 0.15 evidence for PIs have poor BA due to extensive metabolism by Darunavir – 0.055 TDM) CYP450 especially via CYP 3A4 Fosamprenavir – Serious adverse drugs effects of PI: dyslipidaemia, 0.4 insulin resistance, lipodystrophy & Indinavir – 0.1 cardiovascular disease Lopinavir/ritonavir- Lower than standard dose of PIs can provide 1.0 adequate plasma concentrations → able to Nelfinavir – 0.8 maintain virological suppression, Ritonavir – 2.1 especially among Asians. Saquinavir – 0.1 E.g. A lower-dose regimen of indinavir/ritonavir Tipranavir – 20.5 400/100 mg q12h recommended for Thai patients due to high incidence of kidney stones & lipodystrophy syndrome with usual dose of 800/100 q12h. THANK YOU