Khoerul Anwar

▪ Lean body mass (massa

tubuh tanpa lemak) --
mengandung semua
protein -- penting untuk
survival
▪ Fat mass (massa lemak)
-- cadangan energi
▪ Tinggi 172 cm
▪ BB 64 kg
▪ BMI = ??
▪ Pendosisan berbasis berat badan (kgBB) yang diasumsikan untuk
BMI normal, dapat bermasalah pada pasien obesitas dan protein-
energy malnourished.
▪ Penggunaan total body weight, lean body weight, dan atau adjusted
body weight tergantung pada obat dan status obesitas atau
malnutrisi.
▪ Respon klinis terhadap pengobatan bervariasi antar individu – salah
satu penyebab adalah status nutrisi.
▪ Banyak dosis obat berbasis berat badan (mg/kgBB).
▪ Dosis awal (initial dose) dan dosis muatan (loading dose) tergantung
Vd, sedangkan dosis perawatan (maintenance doses) tergantung
klirens.
▪ BMI tidak serta merta bisa diterapkan dalam penentuan dosis obat
karena tidak bisa membedakan massa lemak dan otot (protein).
▪ Body mass index (BMI) 30 atau lebih.
▪ Dianggap suatu “disease” oleh the American Medical Association
(AMA) pada tahun 2013.
▪ Memerlukan rangkaian intervensi medis untuk treatmen lanjutan dan
pencegahannya.
▪ Absorbsi
▪ Distribusi
▪ Metabolisme
▪ Eliminasi
▪ Information currently available on the absorption and bioavailability
of medications in the obese population is scarce and inconclusive.
▪ Limited studies included a study comparing the absorption and
bioavailability of metformin between patients underwent gastric
bypass surgery and their BMI-matched (nonsurgery) cohorts showed
a 50% increase of bioavailability in the surgery group after the
surgery (Padwal et al, 2011).
▪ Another study comparing oral atorvastatin exposure before and after
gastric bypass surgery in the same patient showed variable results
(Skottheim et al, 2009).
▪ Drug distribution, measured as volume of distribution (VD), is
influenced by the size of the tissue, tissue perfusion, plasma protein
binding, tissue membrane permeability, etc (Rowland and Tozer,
2011).
▪ The obese individuals have an increased total tissue mass and
adipose tissue mass (Cheymol, 1993, 2000)→ VD for many drugs may
be increased.
▪ Studies have shown that physicochemical characteristics of the drug,
namely, lipophilicity, plays a major role in the drug distribution
(Cheymol, 1988; Medico and Walsh, 2010) in the obese population.
▪ Generally, in the obese patients, lipophilic medications showed a
larger increased VD, and hydrophilic medications showed a less
increased VD, as compared to the non-obese patients.
▪ There are exceptions to this rule (Flechner et al, 1989; Wojcicki et
al, 2003).
▪ For example, cyclosporine is highly lipophilic, VD in non-obese
patients was 295 L, but in obese patients, was only 229 L.
▪ The concentrations of plasma binding proteins—albumin, α1-acid
glycoprotein, and lipoproteins—may be unchanged (albumin),
increased or decreased (α1-acid glycoprotein) with obesity, resulted
in an altered concentration of the unbound drug.
▪ At present, the impact of obesity on plasma protein binding of
medications is still largely inconclusive.
▪ Drug metabolism primarily occurs in the liver through Phase I
reactions and Phase II conjugation.
▪ A majority of the obese patients have fatty infiltration in the liver
(Moretto et al, 2003), resulted in nonalcoholic fatty liver disease
(NAFLD), with or without inflammation of the liver.
▪ Therefore, the Phase I and II enzyme activities in obesity may be
affected by the fatty infiltration of the liver and its associated
changes.
▪ Cytochrome P450 (CYP) 3A4
▪ It has been reported that CYP 3A4 metabolic activity was reduced in the obese patients, either
significantly, as for carbamazepine and triazolam (Abernethy et al, 1984; Caraco et al, 1995), or
not significantly, as for midazolam and cyclosporine (Greenblatt et al, 1984; Yee, 1988), when
compared to the non-obese patients.
▪ The weight-normalized clearances were invariably lower in the obese patients.

▪ CYP2E1
▪ Various studies showed consistent and significant increases in the clearance of CYP 2E1
substrates in the obese patients, including chlorzoxazone, enflurane, sevoflurane, and
halothane (Miller et al, 1980; Bentley et al, 1982; Higuchi et al, 1993; Lucas et al, 1999; Emery et
al, 2003).
▪ CYP2E1 mediates the metabolism of fatty acids, ketones, and ethanol. Chronic exposure to the
sesubstrates in large amount induces CYP2E1, leading to free-radical formation, lipid
peroxidation, and liver injury (Lieber, 2004; Buechler and Weiss, 2011).
▪ Fatty infiltration of the liver is likely to rise with increasing body weight, which may be the
underlying cause of the increase in CYP2E1 enzyme activity (Brill et al, 2012).
▪ CYP2D6
▪ Studies on dexfenfluramine and nebivolol showed a trend toward increased CYP2D6 activity in
the obese patients (Cheymol et al, 1995, 1997). However, its activity may vary based on its
genetic polymorphisms (May, 1994; Van den Anker, 2010).
▪ CYP1A2
▪ Studies on caffeine and theophylline showed a trend of higher clearance in the obese group,
indicating a slight increase in CYP1A2 activity in the obese patients (Jusko et al, 1979;
Abernethy et al, 1985; Kamimori et al, 1987; Zahorska-Markiewicz et al, 1996).
▪ CYP2C9
▪ Studies on glimepiride and ibuprofen showed a small but significantly increased CYP2C9
activity in the obese patients (Abernethy and Greenblatt, 1985a; Shukla et al, 2004), and studies
on glipizide and phenytoin showed an insignificant increase in the obese group (Abernethy and
Greenblatt, 1985b; Jaber et al, 1996).
▪ While normalized for body weight, a lower enzyme activity of CYP2C9 was associated with the
obese group.
▪ CYP2C19
▪ The only one study for CYP2C19 activities showed that the clearance of diazepam was
significantly higher in the obese group, and no difference was shown for desmethyldiazepam
(Abernethy et al, 1981a, 1982a).
▪ While adjusted for body weight, a lower enzyme activity was shown in the obese group for both
drugs.
▪ Xanthine oxidase
▪ Studies in comparing xanthine oxidase activities using caffeine (Chiney et al, 2011) and
mercaptopurine (Balis, 1986) in the obese versus non-obese children showed significantly
increased enzyme activity in the obese group.
▪ Uridine diphosphate glucuronosyltransferase (UGT)
▪ UGT enzymes catalyze the conjugation of endogenous substances and exogenous compounds,
and are involved in approximately 50% of the Phase II metabolism for drugs.
▪ Since the liver is the main organ for UGT enzyme activities, liver disease or an increased size of
the liver, as occurred in the obese patients, may correlate with UGT activities.
▪ Studies showed a significantly increased clearance in the obese group for medications
metabolized via this pathway, including acetaminophen in adults (Brill et al, 2012), oxazepam,
and lorazepam (Abernethy et al, 1982b, 1983).
▪ With the exception of oxazepam, the weight-normalized clearance values were either the same
or slightly lower in the obese group.
▪ Other Phase II metabolic enzymes
▪ Besides UGT, other Phase II metabolic processes include N-acetyl-, methyl, glutathione, and
sulfate conjugation of substrates.
▪ The study on procainamide, which is metabolized via N-acetylation, showed an increased, but
not statistically significant, plasma clearance in the obese group (Christoff et al, 1983). The
weight-normalized clearance for procainamide was lower in the obese group.
▪ As for studies with busulfan, which is metabolized via glutathione S-transferase, showed a
significantly increased Cl/F in the obese group, while the weight-normalized clearance was
significantly lower in the obese group (Gibbs et al, 1999).
▪ Blood flow in the liver
▪ Obesity is associated with absolute increases in cardiac output and blood volume, as compared
to non-obese subjects (Alexander et al, 1962; Alexander, 1964).
▪ Yet the effect of obesity on liver blood flow is not fully determined, partly because nonalcoholic
fatty liver disease increases fat deposition in the liver, resulting in sinusoidal narrowing and
altered morphology of the liver (Farrell et al, 2008).
▪ Drugs with high-extraction ratio, such as propofol, sufentanil, and paclitaxel, could potentially
serve as markers of liver blood flow, because they are rapidly metabolized and sensitive to
changes in the blood flow of the liver, and less sensitive to changes in enzyme activities. Studies
of these drugs showed higher clearances in the obese subjects (Schwartz et al, 1991;
Sparreboom et al, 2007; Cortinez et al, 2010; Van Kralingen et al, 2011).
▪ However, studies on propranolol, a drug with high-extraction ratio but less clearance rate,
showed variable results (Cheymol et al, 1997; Wojcicki et al, 2003).
▪ Many drugs are eliminated through kidney via glomerular filtration,
tubular secretion, and tubular reabsorption.
▪ The size of the kidney, renal plasma flow, and urine flow rate may
influence the function of the kidney.
▪ Studies comparing clearance of drugs that are primarily eliminated
by glomerular filtration showed a significantly higher clearance in
the obese group for vancomycin (Bauer et al, 1998), daptomycin
(Dvorchik and Damphousse, 2005), and enoxaparin (Barras et al,
2009).
▪ Studies for carboplatin (Sparreboom et al, 2007) and dalteparin (Yee
and Duffull, 2000) showed higher clearances in the obese group, but
not statistically significant as compared to the non-obese group.
▪ A significantly higher tubular secretion in the obese group was
reported for procainamide, ciprofloxacin, and cisplatin (Christoff et
al, 1983; Allard et al, 1993; Sparreboom et al, 2007).
▪ Studies for topotecan and digoxin (Abernethy et al, 1981b;
Sparreboom et al, 2007) showed a trend toward higher tubular
secretion in the obese group, but the difference was not statistically
significant.
▪ It appears that tubular reabsorption of lithium was significantly lower
in the obese group as compared with the non-obese group in the one
study available (Reiss et al, 1994).
▪ In this study, the renal clearance of lithium was significantly increased
in the obese patients, while their glomerular filtration rates were not
different between obese and non-obese groups.
▪ Studies for various drugs have been conducted to evaluate
appropriate dosing regimens for obese patients.
▪ It is not possible to list all the studies and dosing recommendations in
this text.
▪ However, based on the findings from the pharmacokinetic studies,
principles of drug dosing for the obese patients may be adopted to
calculate loading dose and maintenance dose.
▪ The loading dose is primarily based on VD.
▪ In general, the weight used to calculate the loading dose depends on
how the drug is distributed in the lean and fat tissues in the body.
▪ If the drug is primarily distributed into the lean mass, IBW will be
used to calculate the loading dose.
▪ In contrast, if the drug is largely distributed into the fat tissues, TBW
will be used.
▪ If the distribution is somewhere in between, an adjusted weight may
be used (Allen, 2008).
▪ The maintenance dose primarily depends on drug clearance (Cl).
▪ The most commonly used equations to estimate glomerular filtration
rate (GFR) are Cockcroft–Gault (CG) equation (Cockcroft and Gault,
1976) and Modification of Diet in Renal Disease (MDRD) equation
(Levey et al, 1999).
▪ The MDRD equation was developed with six variables—age, gender,
Scr, blood urea nitrogen, albumin, and race—to estimate GFR in
patients with chronic kidney disease.
▪ The CG equation estimates creatinine clearance (Clcr) as a surrogate of GFR.
[(140 – age) × (Weight in kg)]/[72 × serum creatinine] × 0.85 if female
▪ Clearance of the endogenous creatinine in serum (Scr) is dependent on GFR and
renal tubular secretion.
▪ The production of the endogenous creatinine is affected by diet and muscle mass.
▪ To estimate Clcr by the CG equation, it is recommended to use TBW in
underweight patients, IBW in patients with normal weight, and adjusted body
weight for overweight, obese, and morbidly obese patients (Winter et al, 2012).
▪ A recent study (Pai, 2010) reported that using lean body weight (LBW) in the CG
equation provides a practical estimation of GFR for drug dosing in obesity.
▪ A 50-year-old female, BT, was admitted to the hospital with sepsis.
Her height is 5 feet and 5 inches, and weight was 350 lb. Her serum
creatinine is 1.2 mg/dL. The team has decided to start BT on an
antibiotic regimen.
▪ First, calculate BMI for BT
▪ Her TBW in kilogram = 350 (lb)/2.2 (lb/kg), which is 159.1 kg
Her height in centimeter (cm) = 65 (inches) × 2.54 (cm/inch), which is 165.1 cm
Her BMI = 58.4 kg/m2
She is morbidly obese
▪ It is recommended to use adjusted body weight to estimate Clcr from the CG
equation for patients who are overweight, obese, or morbidly obese.
▪ In order to calculate Adj. BW, IBW needs to be calculated first
IBW = 45.5 + 2.3 × [Height (inches) – 60] kg
Her IBW = 57 kg
▪ Calculate Adj. BW
Adj. BW = IBW + 0.4 × (TBW – IBW) kg
Her Adj. BW = 97.8 kg
▪ Calculate Clcr (mL/min) by CG equation using Adj. BW
Clcr (mL/min) = [(140-age) × (Weight in kg)]/[72 × serum creatinine] × 0.85
Her estimated Clcr = 87 mL/min
▪ A 45-year-old male was admitted to the hospital with chief
complaints of shortness of breath, wheezing, chills, and fever. Past
medical history included hypertension, arthritis, and asthma. The
patient’s weight and height were 300 lb and 5′-4″, respectively, and
his serum creatinine is 1.2 mg/dL.
▪ Calculate BMI as in Example 1; the answer is 51.6 kg/m2.
▪ Calculate IBW
IBW = 50 + 2.3 × [Height (inches) – 60] kg
His IBW = 59.2 kg
▪ Calculate Adj. BW as in Example 1
His Adj. BW = 90 kg
▪ Calculate Clcr (mL/min) using Adj. BW for weight
Clcr (mL/min) = [(140 – age) × (Weight in kg)]/(72 × serum creatinine)
His estimated Clcr = 99 mL/min
▪ Malnutrisi protein – malnutrisi yang paling umm terjadi
▪ Individu dengan PCM mengalami penurunan baik jaringan lemak
maupun protein (otot skelet dan berat organ).
▪ Tergantung pada keparahan PCM, umumnya FM sekitar 5% berat
badan dibandingkan normal 20–25%.
▪ Volume cairan ekstraseluler naik menjadi sekitar 20 - 40% berat
badan.
▪ Penurunan massa tubuh, baik lean body mass maupun jaringan
adiposa
▪ Penurunan kardiak output dan aliran darah hepatik
▪ Penurunan kecepatan filtrasi glomerolus (GFR)
▪ Terjadi perubahan metabolisme hepar dan sintesis protein
▪ Terjadu perubahan kadar protein plasma
▪ Perubahan komposisi tubuh yang diikuti dengan penurunan
transport protein dan hormon akan mempengaruhi distribusi obat
▪ Penurunan kardiak output, GFR, berat dan fungsi organ akan
mempengaruhi eliminasi obat
▪ VD obat bisa naik atau turun pada PCM.
▪ PCM yang parah akan menurunkan metabolisme oksidatif dan reaksi
konjugasi.
▪ Cl obat bisa berkurang atau tidak berubah pada PCM
▪ PCM yang ringan bisa jdi berefek atau tidak berefek pada klirens
hepatik oleh cytochrome-P450 (CYP) isoenzymes.
A 45-year-old female was admitted to the hospital with chief complaints of shortness
of breath, wheezing, chills, and fever. Past medical history included hypertension,
arthritis, and asthma. The patient’s weight and height were 300 lb and 5′-4″,
respectively.

1. Which of the following answers is correct for this patient’s body mass index (BMI)?
a. 35.0 d. 54.2
b. 39.3 e. 51.6
c. 60.9

2. If this patient has a serum creatinine of 1.0 mg/dL, calculate her estimated
creatinine clearance in mL/min using adjusted body weight (Adj. BW) in the
Cockcroft–Gault equation.
a. 115.3 d. 152.9
b. 98.0 e. 120.0
c. 61.3
3. Which of the following CYP450 isoenzymes showed a reduced activity in the obese
patients?
a. CYP3A4
b. CYP2E1
c. CYP2C9
d. CYP2D6
e. Xanthine oxidase

4. Which of the following statements most accurately reflects the physiological

changes commonly occurred with obesity?
a. Glomerular filtration is usually increased in the obese patients.
b. Tubular reabsorption is usually increased in the obese patients.
c. Tubular secretion is usually decreased in the obese patients.
d. The activity of uridine diphosphate glucuronosyltransferase is usually
decreased in the obese patients.
e. The size of the kidney is usually smaller in the obese patients.
5. Which of the following statements most accurately reflects an appropriate drug
dosing strategy for the obese patients?
a. The TBW should always be used to calculate the loading dose for the obese
patients.
b. The IBW should always be used to calculate the loading dose for the obese
patients.
c. The TBW should always be used to calculate the maintenance dose for the
obese patients.
d. The IBW should always be used to calculate the maintenance dose for the
obese patients.
e. Applying the pharmacokinetic principles and using modified weight strategies,
combining with therapeutic drug monitoring.