S. Balakrishnan Department of Pharmacology, Pondicherry Institute of Medical Sciences

S. Balakrishnan

Department of Pharmacology,

Pondicherry Institute of Medical Sciences

Absorption

How long it takes after absorption till drug is detectable? (lag time or tlag).

How long it takes before peak – serum or plasma concentration are achieved (tmax).

What is the peak serum concentration? (Cmax)

Absorption problems 1

Vomiting patient

Ketoconazole needs acid

Patients on proton pump inhibitors

(PPI), H2 blockers

Take with Coca Cola

Absorption problems-2

Quinolones (ciprofloxacin) Bind to antacids, sucralfate

Solution: PPI or H2 blocker

Didanosine (ddI) unstable in acid; so: antacid in the tablet

Drugs taken with (out) food

Distribution

Changing Vd

Gentamicin distributes into space resembling extracellular fluid (ECF)

ECF larger in shock, drops with recovery

Gentamicin levels lower in shock, rise with recovery

Limited distribution-1

Most antibiotics well distributed, but ...

Not always intracellular

Not always to:Central nervous systemEye Prostate BonePlacenta Breast milk

Limited distribution-2

Meningitis: Higher doses to get adequate CNS levels

Prostatitis: Prefer trimethoprim-sulfamethoxazole, quinolones

Intracellular penetration

pH- only basic drugs penetrate

Beta lactams ansd AGs- NO

Quinolones and macrolides-YES

Distribution to placenta & breast milk

Hard to predict

Practical matter: look up data on a drug

Plasma protein binding

Unbound drug exerts effect.

Unbound drug diffuses into extra vascular sites.

Slows rate of elimination - & t½ - longer dosing interval.

Significant only if > 80%

Extensive protein binding

“Good”: Allows slow, steady release of heavily bound drug, e.g. ceftriaxone

“Bad”: since less “free” drug available for bacteria, e.g. Ceftriaxone

Reality: Only one factor

Protein binding perinatal issue

Sulfonamide displaces unconjugated bilirubin from serum protein

Perinatally, high unbound bilirubin causes kernicterus & brain damage

Don’t use sulfonamides in 3rd trimester, neonate

Biotransformation

Phase I

Phase II

Biotransformation: CYP 450

Often hepatic microsomal enzymes (CYP 450)

Rates vary up to 6-fold from one person to the next

Enzymes genetically determined

Biotransformation: HIV & TB

Rifampin (for TB) induces CYP450 3A4 & reduces levels of indinavir (for HIV)

Indinavir inhibits CYP450 3A4 & increases levels of rifampin

Solution: Low dose rifabutin, high dose indinavir

Biotransformation: ketoconazole, erythromycin

Ketoconazole, erythomycin inhibit CYP450 3A4

Slows metabolism of cisapride, levels rise, causes torsade de pointes, death

Cisapride highly restricted

Bioavailability

IV to oral switch

Elimination

Renal vs non renal clearanceElimination t1/2

General concept: Elimination t1/2

Half-life

Time for serum concentration to fall

50%

Constant if a person is stable

Varies from person to person

Concentration- time curve

Extravascularconcentration

Extracellular sites reached via diffusion from blood

Intracellular fluid

Extracellular sites with restrictive barriers

Urine

General concept: Clearance

Quantitative measure of body’s

ability to eliminate the drug

Includes various forms of excretion

Antimicrobial concept: MIC, MBC

MIC: Minimum inhibitory concentration (to inhibit growth in vitro)

MBC: Minimum bactericidal concentration (to kill in vitro)

MIC90: Inhibits 90% of strains

Break point

Is in part concentration which can be achieved at the site of infection

Susceptible: MIC < breakpoint

Resistant: MIC > breakpoint

Post-antibiotic effect

Persistence of effect (inhibition of

growth or killing) after drug

removed (or level below MIC)

“PAE” + pharmacokinetics affects

dosing strategy

Post-antibiotic effect

Post antibiotic sub – MIC effects

Post antibiotic – leukocyte effects

Important PK/PD ParametersImportant PK/PD Parameters

Time above MIC

Time

An

tib

ioti

c c

on

cen

trati

on

(u

g/m

l)

2

Drug A

Drug B

A

B

4

6

8

0

Important PK/PD Parameters

Drug A

Drug B

B

Proportion of the dosing interval when the drug concentration exceeds the MIC

Time above MIC:

Important PK/PD Parameters

An

tib

ioti

c

con

cen

trati

on

Time

Area under the curve over MIC

PEAK

AUC/MIC is the ratio of the AUC to MICPeak/MICis the ratio of the peak concentration to MIC

PK/PD and Antimicrobial Efficacy

2 main patterns of bacterial killing Concentration dependent

Aminoglycosides, quinolones, macrolides, azalides, clindamycin, tetracyclines, glycopeptides, oxazolidinones

Correlated with AUC/MIC , Peak/MIC

Time dependent with no persistent effectBeta lactamsCorrelated with Time above MIC(T>MIC)

Goal of therapy based on PK/PD

Pattern of Activity

Antimicrobials Goal of therapy and relevant PK/PD

Parameter

Concentration dependent killing

AGs, Quinolones, Daptomycin, ketolides, Macrolides, azithro-mycin, clindamycin,streptogramines,tetracyclines, glycopeptides, oxazolidinones

Maximise concentrations; AUC/MIC, peak/MICUse high doses; daily dosing for some agents

Time dependent killing with no persistent effects

Beta lactams Maximise duration of exposure; T>MICUse more frequent dosing; longer infusion times including continuous infusion

Pattern of Activity Antibiotics Goal of

Therapy PK/PD

Parameter

Type IConcentration-dependent killing andProlonged persistent effects

AminoglycosidesDaptomycinFluoroquinolonesKetolides

Maximize concentrations

24h-AUC/MICPeak/MIC

Type IITime-dependent killing and Minimal persistent effects

CarbapenemsCephalosporinsErythromycinLinezolidPenicillins

Maximize duration of exposure

T>MIC

Type IIITime-dependent killing andModerate to prolonged persistent effects.

AzithromycinClindamycinOxazolidinonesTetracyclinesVancomycin

Maximize amount of drug

24h-AUC/MIC

Magnitude of PK/PD measures predictive of efficacy for select antibiotic classes versus some pathogens

Drug PK/PD variable Magnitude of variable correlated with efficacy

Beta lactams Time > MIC >40-50% of dosing interval

Quinolones vs Gram –ve bacteria

24- hour AUC:MIC >90-125

Quinolones vs S. pneumoniae

24-hour AUC:MIC >30-40

Aminoglycoside pharmacodynamics in vivo

Vancomycin Outcome vs 24h-AUC/ MIC ratio

24h-AUC/MIC ratio

Satisfactory Unsatisfactory

< 125 4 (50%) 4

> 125 71 (97%) 2

24h-AUC/MIC ratio

Microbiological Response

< 33.7 (64%)

> 33.7 (100%)

Fluoroquinolone PK/PD vs S. pneumoniae

PK/PD of beta-lactams and macrolides in otitis media

Concentration dependent killing….azithromycin

•24 hour AUC/ 25-immunocompetent patients

•24 hour AUC/ 125- immnocompromised

patients

•24 hour AUC mg.h/ L -3 mg.h/L

•Macrolide susceptible S.pneumoniae MIC90 0.12

mg/L

•H. Influenzae MIC90 1-2mg/L

•Macrolide resistant S. pneumoniae MIC90

>8mg/L

PK/PD breakpoints of parenteral beta-lactams based on serum concentrations present for >40-50% of dosing regimens shown and MIC90 values of isolates of S. pneumoniae

Drug Dosing regimen

S.Pneumoniae MIC90 mg/L

PK/PD breakpoint mg/L

Pen G 2 X 106 U qid 4 4

Ampicillin 1 g qid 4 2

Cefuroxime 0.75 g tid 8 4

Cefotaxime 1 g tid 2 2

Ceftriaxone 1 g qd 2 2

Cefepime 1 g bid 4 4

Ceftazidime 1 g tid 32 8

Meropenem 0.5 g tid 2 1

Dosage Adjustment Needed in Renal Impairment I

Acyclovir ethambutol

aminoglycosides, Penicillins (except antistaph)

aztreonam, Quinolones

cephalosporins (except cefaperazone & ceftriaxone)

clarithromycin, Carbapenems

daptomycin, Vancomycin

doripenem, emtricitabine,

famiclovir, ertapenem,

flucytosine, ganciclovir,

imipenem, meropenem,

lamivudine, foscarnet,

fluconazole,

Dosage Adjustment Needed in Renal Impairment II

C/I in renal failure

MethanamineNalidixic acidNitrofurantoinSulfonamidesTetracyclines except doxy &

minocycline

Dosage adjust in hepatic impairment

Chloramphenicol

Clindamycin

Erythromycin

Metronidazole

Tigecycline