Transcript Document
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 system
Eye
Prostate
Placenta
Breast milk
Bone
Limited distribution-2
Meningitis: Higher doses to get adequate
CNS levels
Prostatitis: Prefer trimethoprimsulfamethoxazole, 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 clearance
Elimination 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 Parameters
Parameters
Important PK/PD
Time above
MIC:
Proportion of the
dosing interval
when the drug
concentration
exceeds the MIC
Antibiotic concentration
(ug/ml)
8
6
4
Drug A
Drug A
Drug B
Drug B
2
B
B
0
A
Time above MIC
Time
AUC/MIC
is the ratio of the
AUC to MIC
Peak/MIC
is the ratio of the
peak
concentration to
MIC
Antibiotic
concentration
Important PK/PD Parameters
Area under the curve
over MIC
PEAK
Time
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 effect
Beta lactams
Correlated 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 AGs, Quinolones,
dependent
Daptomycin, ketolides,
killing
Macrolides, azithro-mycin,
clindamycin,streptogramines
,tetracyclines, glycopeptides,
oxazolidinones
Maximise concentrations;
AUC/MIC, peak/MIC
Use high doses; daily
dosing for some agents
Time
Beta lactams
dependent
killing with no
persistent
effects
Maximise duration of
exposure; T>MIC
Use more frequent dosing;
longer infusion times
including continuous
infusion
Pattern of Activity
Antibiotics
Goal of
Therapy
PK/PD
Parameter
Type I
Concentrationdependent killing and
Prolonged persistent
effects
Aminoglycosides
Daptomycin
Fluoroquinolones
Ketolides
Maximize
24h-AUC/MIC
concentratio
Peak/MIC
ns
Type II
Time-dependent killing
and
Minimal persistent
effects
Carbapenems
Cephalosporins
Erythromycin
Linezolid
Penicillins
Maximize
duration of
exposure
T>MIC
Type III
Time-dependent killing
and
Moderate to prolonged
persistent effects.
Azithromycin
Clindamycin
Oxazolidinones
Tetracyclines
Vancomycin
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.
24-hour AUC:MIC
>30-40
pneumoniae
Aminoglycoside pharmacodynamics
in vivo
Vancomycin Outcome vs 24h-AUC/
MIC ratio
24hAUC/MIC
ratio
Satisfactory
Unsatisfactory
< 125
4 (50%)
4
> 125
71 (97%)
2
Fluoroquinolone PK/PD vs S.
pneumoniae
24h-AUC/MIC
ratio
Microbiological
Response
< 33.7
(64%)
> 33.7
(100%)
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.Pneumonia PK/PD
e MIC90 mg/L breakpoint
mg/L
Pen G
2 X 106 U qid
4
4
Ampicillin
Cefuroxime
Cefotaxime
Ceftriaxone
1 g qid
0.75 g tid
1 g tid
1 g qd
4
8
2
2
2
4
2
2
Cefepime
Ceftazidime
Meropenem
1 g bid
1 g tid
0.5 g tid
4
32
2
4
8
1
Dosage Adjustment Needed in
Renal Impairment I
Acyclovir
ethambutol
aminoglycosides,
Penicillins (except
antistaph)
aztreonam,
Quinolones
cephalosporins (except cefaperazone &
ceftriaxone)
clarithromycin,
Carbapenems
Dosage Adjustment Needed in
Renal Impairment II
daptomycin,
Vancomycin
doripenem,
emtricitabine,
famiclovir,
ertapenem,
flucytosine,
ganciclovir,
imipenem,
meropenem,
lamivudine,
foscarnet,
fluconazole,
C/I in renal failure
Methanamine
Nalidixic acid
Nitrofurantoin
Sulfonamides
Tetracyclines except doxy & minocycline
Dosage adjust in hepatic impairment
Chloramphenicol
Clindamycin
Erythromycin
Metronidazole
Tigecycline