Clinical pharmacokinetics Flashcards
First in human studies
need to identify a human equivalent dose based on a no adverse effects level (NOAEL) in low risk compounds.
Animal dose to human dose is based on body surface area normalisation.
A safety factor is used in the FIH dose - normally 10. divide the human equivalent dose by 10. higher safety factor may be used if it had severe toxicity in animals. This gives the MRSD - recommended maximum dose for first into man.
MABEL
human equivalent dose for first in human dose is calculated from the minimal anticipated biological effective level (MABEL) for high risk compounds. high risk due to little info about target, target active in multiple signalling pathways, or target is widely expressed. MABEL was proposed following TGN1412. a dose where only slight pharmacological activity is observed - no single method of calculation.
Mode of action, pharmacology of target, relevance of animal models, and patient population are considered to determine the MABEL
End points and analysis of phase 1 data
to determine MTD and optimal biological dose (OBD) - needed to design dosing strategies for phase 2.
some identification of target interactions and off-target effects.
Plasma is attained from FIH studies and PK such as Vd, CL, AUC, F, MRT, t1/2, Cmax and Tmax are calculated (often by NCA). determines dose escalation studies (either single ascending or multiple ascending doses)
Endpoints and analysis of phase 2 and 3 clinical trials
Phase 2 to determine the relationship between dose and effect. determine minimum and maximum effective doses. therapeutic index
phase 3 to confirm the PKPD relationship and identify sources of variation
Compartmental models are used to characterise the PK parameters here.
Effect of diet on PK
Diet can effect gastric emptying, e.g., vegetarians see lower Tmax and Cmax of paracetamol. prolonged gastric emptying
Drug-food interactions may occur, such as grapefruit which inhibits CYP3A4 - increases bioavailability and t1/2, decreases clearance.
Smoking and alcohol effect on PK
cigarettes induce CYP1A2, increasing the clearance of antipsychotics, e.g., olanzapine which has 5-fold lower exposure in smokers
Alcohol effects gastric emptying and can induce or inhibit CYP2E1 depending on frequency of intake. interactions with isoniazid and paracetamol are seen
Changes in absorption in children
Gastric pH is neutral at birth and only reaches adult pHs at age 2. protects acid liable drugs and sees high beta-lactam bioavailability. low bioavailability of phenytoin, paracetamol, and phenobarbital
Gastric emptying is slowed and reduced [bile salts]. Also variable levels of hepatic and extra-hepatic CYP. ultimately sees decreased rate of absorption
Changes in distribution in children
Body composition changes as we age. redistribution of body water and fat occurs, with fat increasing in early life. alters Vd of fat/water soluble drugs. fat increases 4-5-fold in first year
Infants tend to have lower levels of plasma proteins. they have especially lower AAG (50%) levels compared to albumin (80%). can lead to more free drug, high Vd, and greater distribution out of the blood.
the BBB can also be immature, leading to heightened permeability
changes in metabolism in children
continual non-linear physiological and biochemical changes from birth, e.g., changes in the contribution of UGT and SULT enzymatic pathways
paediatrics show precise ontogeny patterns in the expression of drug metabolising enzymes. as such age-related dosing regimens are needed, especially for high clearance drugs.
CYP levels increase within first weeks of life, but some slower than others, e.g., CYP1A2. by 2-5y, most CYP at adult levels.
some conjugation enzymes are more present in neonates/infants then adults, such as SULT
changes in excretion in children
kidneys are functionally immature at birth. very low GFR. as such, renal cleared drugs will show a progressive decrease in t1/2 with ageing.
Changes in PK in elderly
changes in PK is often confounded by diseases common in the elderly
Oral absorption is delayed or reduced due to lower intestinal blood flow. Gastric pH is raised, altering ionisation and solubility of some drugs. no significant effects compared to adults
Higher fat, lower protein and water, leads to altered Vd, e.g., accumulation of lipophilic drugs e.g., diazepam and decreased Vd of hydrophilic ones, e.g., digoxin
Reduction in serum albumin levels
Liver blood flow is reduced, which can slow clearance rate, but also reduce the first pass effect. no clear evidence of age-related changes in hepatic microsomal protein content. limited changes in metabolism.
Kidney mass decreases and glomeruli number decreases by 20-30% by 80. cofounding factors such as diabetes can contribute to reduced GFR. in absence of disease GFR is not greatly affected
absorption changes in pregnancy
gastric emptying slowed. would reduce Cmax, increase Tmax.
distribution changes in pregnancy
Total blood volume and plasma volume increase up to 50%. hydrophilic drugs will have higher Vd - Cmax decreases. may not be clinically relevant due to changes in PPB
the decreased ratio of lean mass to adipose tissue can lead to greater Vd of lipophilic drugs
Albumin and AAg decrease leading to more free drug. this can increase drug distribution however
metabolism changes in pregnancy
Drugs that are highly protein bound may see higher clearance, such as valproic acid.
the liver sees increased blood flow by about 60%, which can increase the metabolism of drugs -thus clearance, such as morphine which has 60-70% greater clearance
Hormones such as oestrogen’s, cortisol and progesterone can induce or inhibit CYP enzymes. the expression of different CYPs is gestational-age dependent, e.g., CYP3A4 increases up until week 20, where it then decreases almost back to baseline levels by week 40. CYP1A2 continually decreases, and CYP 2D6 increases and then begins to plateau in later weeks
excretion changes in pregnancy
GFR is 50% higher by the first trimester and continually increases until the last week of pregnancy. Cefazolin and clindamycin see increased renal clearance
lithium clearance is doubled during third trimester
