Clinical Pharmacokinetics Module 8 Alwyn Pidgen February 2013

1. Clinical Pharmacokinetics Module 8 Alwyn Pidgen February 2013

2. The importance of PK information • Supports decision making throughout drug development • Essential to satisfy global regulatory requirements • Aids the interpretation of PD findings • Contributes significantly to global bridging packages (e.g. Japanese filing) Plasma concentrations are the most widely used surrogate

3. ABSORPTION • Is the the transfer of a substance from the site of administration into the systemic circulation • Is measured in terms of both rate & extent • For drugs administered extravascularly – absorption is a pre-requisite for systemic activity. • For drugs administered intraveneously, absorption is not involved and the substance enters the circulatory system immediately.

4. Common Extravascular Routes • Oral • Subcutaneous • Intra-muscular • Topical • Transdermal • Implantation • Sublingual / Buccal • Inhalation • Intranasal • Rectal • The absorption from any route may be affected by; • Physicochemical properties of drug • Characteristics of the formulation and method of delivery • Physiological nature of the tissue or injection site

5. Oral administration • For a drug substance to be absorbed after oral administration, it must first: - • Disintegrate and dissolve (Dissolution) • Favours hydrophilic drugs • Transfer from the stomach into the small intestine (Gastric emptying) • Cross intestinal cell membranes (Drug transport) • Favours lipophilic drugs

6. The oral absorption pathway

7. Dissolution is a major cause of differences in the rate & extent of absorption (e.g. solution v capsule v tablet). • In-vitro dissolution tests can guide the optimisation of drug release from formulations, predict in-vivo performance and ensure quality control of batches.

8. Gastric emptying & Intestinal transit • Gastric emptying from the stomach is a continual process (peristaltic waves). • Food changes gastric motility, with gastric secretions and residence times being increased. • Changes to the pH of the gastric contents can affect a drugs solubility and absorption. • Food is more likely to impact rate rather than extent of absorption. • Most drugs are absorbed from the small intestine • The average transit time through the small intestine is 3-5 hours (absorption window).

9. Transport across membranes • To cross a membrane a drug must be soluble in the lipid material of the membrane (to partition into and across the membrane) and also be soluble in the aqueous phase (to partition out of the membrane and into the blood). • The majority of drugs pass through membranes by passivediffusion

10. Cmax AUC(0-24) • ka • tmax • ka and tmax reflect the rate of absorption • Cmax is influenced by the rate and extent of absorption • AUC(0-24)reflects the extent of absorption to 24h post-dose. Pharmacokinetics of absorption – single oral dose

11. Effect of changes in absorption rate on PK • Changes in ka lead to changes in Cmax and tmax

12. Impact of changes in formulation on PK Fast release Standard release CC Standard release Sustained release t t Standard release C Delayed release t

13. Absolute Bioavailability - F Is the fraction of the administered dose that escapes pre-systemic metabolism and reaches the systemic circulationas unchanged drug. • Ranges between 0 and 1 (or 0 and 100%). • Calculated as AUCextravascular / AUCintravenouscorrected for the difference in dose. • Major factor is hepatic metabolism

14. First pass effect • Following oral administration a drug is subject to loss through: - • Incomplete dissolution • Insufficient time for absorption • Problems in crossing the gut wall membrane • Pre-systemic metabolism by the gut wall & liver • The additive loss of drug on the first pass through these sites is termed the first pass effect. • A high first pass effect can be partially avoided by rectal administration. Also by sublingual& buccal administration.

15. Sites of potential loss after oral dosing

16. DISTRIBUTION • Is the process of drug transfer to and from the various organs and tissues in the general circulation. • At equilibrium drug distribution depends upon binding to both plasma proteins and tissue components. • Definitive information requires measurements in various organs and tissues • Tissue distribution data & WBA (animals) • Plasma drug concentrations (humans)

17. Factors affecting drug distribution (i) Perfusion • Perfusion rates of tissues vary widely. Well perfused tissues (e.g. liver, lung, heart) take up drugs more rapidly than poorly perfused tissues (e.g. fat, muscle skin) (ii) Diffusion • Some drugs have difficulties crossing membranes to reach the site of action. • Lipid soluble drugs pass through very rapidly. • Water soluble and/or large molecule drugs penetrate more slowly

18. (iii) Plasma Protein Binding • Many drugs bind to plasma proteins (e,g, albumin, 1-glycoprotein, lipoprotein & globulin). • Binding is a reversible phenomenon – rates of association & disassociation are rapid • It is the free (unbound) drug in plasma which is linked to efficacious or toxic responses. Can become clinically relevant when >95% is protein bound (e.g. warfarin). • Competition or displacement of a drug from binding sites may lead to increases in free drug concentrations and hence toxicity (e.g. drug interactions).

19. (iv) Tissue binding • Only unbound drug is capable of entering & leaving the tissues PlasmaTissue bound bound unbound unbound

20. Volume of Distribution (V) • Is the theoretical volume of fluid into which the total drug administered would have to be diluted in order to produce the concentration seen in plasma. Vinitial = Amount of drug in body =Dose Plasma drug concentration C(0) Ideally estimated after intravenous dosing. • Other estimates of volume of distribution (Varea and Vss) are sometimes quoted. • Units of V are in litres.

21. Real physiological volumes V = 28L V = 14L V = 5L Total body water = 42L

22. Extensive tissue distribution and/or tissue binding • Only a small fraction of the dose remains in the vascular compartment hence drug concentrations are low • High volume of distribution >> total body water (42L) • Examples – digoxin (490L), pethidine (280L) Extensive plasma protein binding • Plasma protein binding restricts the distribution of drugs to the vascular compartment - hence systemic drug concentrations are high. • Low volume of distribution < extracellular fluid (14L) • Examples: - • warfarin (97% plasma protein bound and V=10L) • tolbutamide (97% plasma protein bound and V=8L)

23. The blood brain barrier • A semi-permeable membrane composed of endothelial cells, packed very tightly in brain capillaries. • This high density restricts the distribution of substances from the bloodstream much more than endothelial cells in capillaries elsewhere in the body • Large molecules do not easily cross the blood brain barrier nor do hydrophilic molecules • Lipid soluble molecules such as Thiopental and other barbiturate drugs rapidly cross into the brain. • Because the nasal mucosa is near the brain, intranasal administration may rapidly achieve therapeutic brain and spinal cord (CNS) drug concentrations.

24. ELIMINATION • Elimination is the irreversible transfer of a drug from the body. • Pathways include: - • Metabolism • Renal excretion • Biliary excretion • Sweat, Breast milk, Saliva, Lungs (exhaled air). • Elimination pathways can be quantified (in animals and humans) by a radiolabelled study.

25. Metabolism • Is the mechanism by which a drug is partially or wholly converted from one chemical form into another. • The liver is the primary site for metabolic conversion. • The metabolic rate depends upon • the lipophilicity of the drug • the amount of drug presented to the liver • Individual differences (e.g. genetic phenotyping) • Metabolism converts lipophilic chemical compounds into more readily excretedhydrophilic products. • A drug that is itself inactive but is rapidly converted into an activecompound through metabolism is called a prodrug (e.g. Enalpril  Enalaprilat)

26. Factors affecting Drug Metabolism Dose level Increased dose  saturation of metabolic enzymes  more parent drug Route of administration Can alter amount of first pass metabolism (e.g. rectal) Species Major differences between animals and man. Age Children & very elderly  different metabolic reactions Disease Changed kinetics in patients with liver disease. Drug interactions Co-administration with other drugs (induction or inhibition).

27. Hepatic Clearance Hepatic blood = Hepatic blood * Hepatic extraction clearance (CLH) flow (QH) extraction ratio (EH) • Two major systems are involved • Mixed function oxidases (cytocrome P450) • Conjugations (e.g. glucuronides, sulphates) • For most drugs the liver has the greatest metabolising capacity with a Hepatic blood flow (QH)~ 1500ml/min. • EH is the fraction of the drug entering the hepatic system which is extracted by the liver. • An estimate of bioavailability is given by F = 1 – EH(assuming no loss of drug prior to hepatic extraction)

28. Hepatic Extraction Ratios(EH) From Clinical Pharmacokinetics – Concepts and Applications by Rowland M and Tozer T.N.

29. Biliary excretion • Can be an important route of elimination for some drugs and their metabolites (e.g. chloramphenicol, morphine, indomethacin). • The liver excretes 0.25 – 1.0 litres of bile each day. • Molecular weights around 500 Dalton are optimal for drugs to be excreted through the bile. • Difficult to measure in man due to the relative inaccessibility of the biliary tract.

30. The renal excretion pathway Processes include Filtration, Re-absorption and Secretion

31. Glomerular Filtration • Most small molecule drugs – not bound to proteins - are filtered by the glomerulus. • Water and drug substances cross the filtration membrane into Bowman’s space • GFR is the rate (ml/min) at which blood is filtered. It is a valuable clinical indicator of renal function and can be approximated by creatinine clearance. • Tubular Re-absorption • As the filtrate passes through the tubules, specific substances are reabsorbed back into the blood of the peritubular capillaries. • Drug re-absorption can be affected by the urine pH of the filtrate. For example,pentobarbital excretion can be increased by making the urine more alkaline. • Tubular Secretion • Some drugs (e.g. penicillin) are actively secreted from the blood into the nephron.

32. Renal excretion of metabolites • The kidney is the principal site for the excretion of unchanged drug. • However, many metabolites formed by the liver are also renally excreted. • The opioid analgesic Fentanyl is metabolised primarily in the liver. Approximately 75% of the dose is excreted in urine mostly as metabolites. Less than 10% is unchanged drug. • Drugs excreted by the kidneys require careful handling in the elderly and patients with renal impairment.

33. Total Clearance (CL) Is the volume of plasma (blood) completely cleared of drug per unit of time (ml/min or litres/h). Clearance reflects the efficiency of drug removal from the body. Total clearance is the sum of all organ clearances CL Total = CL Renal + CL Hepatic + CL Other Can be calculated after intravenous administration as:- CLtot = Dose AUC

34. Renal clearance • The kidney is the principal site for the excretion of parent drug. • In general, hydrophilic (water loving) drugs are predominantly excreted in the urine. • Calculation of Renal Clearance requires both Plasma and Urinary excretion data from the same individual. CLR = Ae AUC

35. Urinary excretion Estimates the amount of unchanged drug excreted by the kidneys. Amount of drug Volume of urine Concentration of excreted per = collected per * unchanged drug in time interval (ug) time interval (ml) urine sample (ug/ml) The sum of all individual urinary excretions gives the total amount excreted unchanged (Ae)

36. ln2 k t1/2 = where ln2 = 0.693 t1/2 t1/2 The terminal half life The terminal half-life (t1/2) is the time taken for the plasma concentration to fall by half (on a log scale) The elimination rate constant k is the slope of the line 2 Log plasma conc’n 1 0.5 Time

37. Log C Time How long does the drug stay in the body? C0 C0/2 t1/2 t1/2 t1/2 95% of drug eliminated ~ 5 t1/2’s

38. The half-life of a drug is the ratio of its Volume and Clearance. t1/2 = 0.693 * V CL Interpreting the Half-life Implications Drugs with long half-lives do not necessarily have low Clearances. For example - Digoxin has a half-life of 1 day – but this is due mainly to a large V (drug is concentrated in the tissues).

39. REPEATED DOSING

40. The majority of drugs are prescribed as repeat dosage regimens • Accumulation (build-up) to steady-state occurs when drug intake exceeds drug elimination. • There is a limit to drug accumulation (called steady-state) where the rate of drug administration (rate in) equals the rate of drug elimination (rate out). • Single dose data can be used to predict steady-state (assuming linear kinetics)

41. Simplified steady-state model • At steady-state a fixed rate of water (e.g. 4 drops/unit time) flows into and out of the bathtub (rate in = rate out) • The bath water stays level (i.e. at steady state) unless one of the rates is changed. • Clearance is determined by the size of the hole in the bathtub.

42. The path to steady-state • Drug with half-life of 6 hours • 100mg i.v. gives a Cp(0) of 4mg/l • The drug levels fall by half - every half-life (6h)

43. The time to reach steady-state is controlled solely by the elimination half-life of the drug. •  95% of steady state is reached within 5 half-lives and  99% is reached within 7 half-lives. • The Dose and Dosing frequency controls the extent of drug accumulation as well as the peak to trough ratio.

44. PK parameters at steady-state • Cssmax – the maximum steady-state concentration • Cssmin – the minimum steady-state concentration • Csav – the average concentration across one dosing interval at steady-state (AUC0- /) • AUC0- - the area under the curve over one dosing interval at steady-state • Cssmax/Cssmin - Peak to Trough ratio (PTR) • (Cssmax - Cssmin) / Cssav– Fluctuation index (FI)

45. Impact of dosing frequency and formulation on PTR Toxic Effective Ineffective D = CR (360mg every 12h) B = CR (180mg every 6h) C = SR (360mg every 12h) A = SR (180mg every 6h) CR = Conventional release SR = Sustained release

46. Dose dependencies • Very important to assess how drug concentrations change with dose or time. • Can have major implications for the dosage regimen – especially in late stage clinical trials. Kinetic linearity (predictability) occurs when:- • Cmax and AUC increase in a proportionate manner to increases in dose • all other variables (e.g. half-life, V, CL) are independent of dose Stationarity (predictability) occurs when:- • the PK characteristics do not change over a (long) period of time (e.g. Phase III study)

47. Linear kinetics Kinetic linearity occurs when:- Group 1: Cmax, AUC and Ae increase in proportion to increases in dose (i.e. dose proportionality) Group 2: t1/2, tmax, V, CL and F remain unchanged following increases in dose Group 1 Group 2 Dose Dose

48. Dose proportionality of the antiviral drug penciclovir Mean + SD of 20 healthy subjects * Cmax and AUC proportional to Dose

49. Non-linearity of Salicylamide The increase in bioavailability is due to a decrease in first-pass effect following the saturation of hepatic metabolism in the liver.

50. Time dependency of Carbamazepine ------ predicted profile actual profile Carbamazepine induces its own metabolism (increased CL) due to a change in turnover of metabolic enzymes.