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S. Balakrishnan
Department of Pharmacology,
Pondicherry Institute of Medical Sciences
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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)
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Absorption problems 1
Vomiting patient
Ketoconazole needs acid
Patients on proton pump inhibitors
(PPI), H2 blockers
Take with Coca Cola
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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
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Distribution
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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
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Limited distribution-1
Most antibiotics well distributed, but ...
Not always intracellular
Not always to:Central nervous systemEye Prostate BonePlacenta Breast milk
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Limited distribution-2
Meningitis: Higher doses to get adequate CNS levels
Prostatitis: Prefer trimethoprim-sulfamethoxazole, quinolones
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Intracellular penetration
pH- only basic drugs penetrate
Beta lactams ansd AGs- NO
Quinolones and macrolides-YES
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Distribution to placenta & breast milk
Hard to predict
Practical matter: look up data on a drug
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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%
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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
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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
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Biotransformation
Phase I
Phase II
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Biotransformation: CYP 450
Often hepatic microsomal enzymes (CYP 450)
Rates vary up to 6-fold from one person to the next
Enzymes genetically determined
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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
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Biotransformation: ketoconazole, erythromycin
Ketoconazole, erythomycin inhibit CYP450 3A4
Slows metabolism of cisapride, levels rise, causes torsade de pointes, death
Cisapride highly restricted
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Bioavailability
IV to oral switch
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Elimination
Renal vs non renal clearanceElimination t1/2
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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
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Concentration- time curve
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Extravascularconcentration
Extracellular sites reached via diffusion from blood
Intracellular fluid
Extracellular sites with restrictive barriers
Urine
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General concept: Clearance
Quantitative measure of body’s
ability to eliminate the drug
Includes various forms of excretion
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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
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Break point
Is in part concentration which can be achieved at the site of infection
Susceptible: MIC < breakpoint
Resistant: MIC > breakpoint
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Post-antibiotic effect
Persistence of effect (inhibition of
growth or killing) after drug
removed (or level below MIC)
“PAE” + pharmacokinetics affects
dosing strategy
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Post-antibiotic effect
Post antibiotic sub – MIC effects
Post antibiotic – leukocyte effects
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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:
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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
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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)
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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
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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
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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
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Aminoglycoside pharmacodynamics in vivo
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Vancomycin Outcome vs 24h-AUC/ MIC ratio
24h-AUC/MIC ratio
Satisfactory Unsatisfactory
< 125 4 (50%) 4
> 125 71 (97%) 2
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24h-AUC/MIC ratio
Microbiological Response
< 33.7 (64%)
> 33.7 (100%)
Fluoroquinolone PK/PD vs S. pneumoniae
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PK/PD of beta-lactams and macrolides in otitis media
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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
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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
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Dosage Adjustment Needed in Renal Impairment I
Acyclovir ethambutol
aminoglycosides, Penicillins (except antistaph)
aztreonam, Quinolones
cephalosporins (except cefaperazone & ceftriaxone)
clarithromycin, Carbapenems
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daptomycin, Vancomycin
doripenem, emtricitabine,
famiclovir, ertapenem,
flucytosine, ganciclovir,
imipenem, meropenem,
lamivudine, foscarnet,
fluconazole,
Dosage Adjustment Needed in Renal Impairment II
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C/I in renal failure
MethanamineNalidixic acidNitrofurantoinSulfonamidesTetracyclines except doxy &
minocycline
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Dosage adjust in hepatic impairment
Chloramphenicol
Clindamycin
Erythromycin
Metronidazole
Tigecycline
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