Case

Review
TB510061 TB510086
` TB510062 TB510087
Student: Rannissa Puspita Jayanti
Tran Minh Hung
Advisor: Jae-Gook Shin, MD, PhD
Co-advisor: Yong-Soon Cho, MD, PhD
Young-Kyung Choi, MSc
 TB510061
Pulmonary TB;
Low plasma concentration (RIF, EMB);
01
Probability of missing data
TB510062
Pulmonary TB
Ultra slow acetylator NAT2
02
TB510086
Pulmonary TB; INH BLLoQ; Long TAD; Neuropathy
Peripheral; Low dosage of Anti-TB drugs
03
TB510087
Pulmonary TB; Multiple ADRs; BLLoQ of INH and 04
STR; Long TAD
Case 1 (TB510061)
• Pulmonary TB; DS-TB
• Low plasma concentration (RIF, EMB)
• Probability of missing data
• M/59 y.o; 48 kg, 160 cm Diagnosis and Medication History
• Dx: Pulmonary TB; DS-TB
• Ex-smoker
• Comorbidity: No
2020.07.27
2020.07.20-27
- 1st TDM
Concomitant medication - Time: 2:30, TAD: 5.5 hours
- Metronidazole, 500 mg, IV, TID - Drug concentration (µg/ml)
- Codeine, 10 mg, PO, TID INH: 1.46 PZA: 21.09
- Paracetamol, 500 mg, PO, TID RIF: 4.26 EMB: 0.55

2020.07.20 2020.07.26
- Dx: Pulmonary TB - Last dose administration:
- Start of treatment: HRZE; PO; fasting state
HRZE, PO, QD (300/450/750/750 mg)
(300/450/750/750) - Time: 21:00
- Single drug combination
 Laboratory Findings
Biochemistry Hematology
Name Normal Range 2020.07.26 Name Normal Range 2020.07.26
ALB 3.8-5.3 g/dL 3.6 WBC 4-10 x 109/L 11.2
TPRO 6.7-8.3 g/dL - RBC 4.2-6.3 x 1012/L -
AST 13-33 U/L 20 HGB 14-18 g/dL 10.9

SaturnALT 6-27
is a gas giant, 26 HCTDespite38-52 %
being red, -
Mars is cold place.
composed mostly of PLT 140-440 x 109/L 342
TBIL
hydrogen 0.2-1.2
and helium 0.69 It’s full of iron oxide
NEU dust
40-80 % 79
UA 3-5.5 mg/dL -
LYM 15-50 % 18.8
BUN 8-22 mg/dL 7
MON 2-11 % 7.5
CR 0.8-1.2 mg/dL 0.6
EOS 1-7 % 1.7
eGFR 110 mL/min/1.73 m2
BAS 0-1 % -
ANC ~ x 109/L -
 Other Tests

• Samples: Sputum and Chest X-ray PGX result

Jupiter is a gas giant
Empyema • No cavitary lung lesion • NAT2: *5/*7; slow
and the biggest
• Xpert: MTB (+); RIF (not • Fibrosis infiltration, pleural acetylator
planet in our Solar
detected) effusion, severe lung lesion • SLCO1B1: *15/*15 ; low
System
transporter function

2020.07.20 2020.07.26 2020.12.31

Pharmacokinetics Results

Drug concentration
• RIF, PZA concentrations are inferior the reference range
• INH concentration is superior the reference range
• EMB concentration is inferior the reference range
Simulation of RIF with Dose 600 mg
Simulation of EMB with Dose 1200 mg
 Scatter Plots of INH

All TDM Data Normalized to Standard Dose 300mg Same Dose 300 mg, QD
 Scatter Plots of RIF

All TDM Data Normalized to Standard Dose 600 mg Same Dose 450 mg, QD
 Scatter Plots of PZA

All TDM Data Normalized to Standard Dose 1500 mg Same Dose 750 mg, QD
 Scatter Plots of EMB

All TDM Data Normalized to Standard Dose 800 mg Same Dose 750 mg, QD
 Medical Issues and Suggestions

PK
- RIF, EMB concentration are inferior the
reference range
- Low dose of RIF (450 mg) and EMB (750
mg)
=> Simulate with dose 600mg for RIF and
1200 mg for EMB, concentrations are with the
reference range
=> Suggest dose 600 mg and 1200 mg for RIF
and EMB
Missing data
Information in treatment and lab tests
- Concomitant medication
- Pleural effusion, empyema
No information of comorbidity
=> Report the CRC to correct data
Case 2 (TB510062)
• Pulmonary TB; DS-TB
• Ultra slow acetylator NAT 2
• M/54 y.o; 58 kg, 165 cm Diagnosis and Medication History
• Dx: Pulmonary TB; DS-TB
• Ex-smoker
• Comorbidity: DM
2020.07.24 2020.07.27 2020.07.28
Concomitant medication - 1st TDM - 2nd TDM
- Levemir SC QD 24 IU - Time: 7:55, TAD: 11.92 hours - Time: 8:15, TAD: 12.25 hours
- Novorapid SC QD 12 IU - Drug concentration (µg/ml) - Drug concentration (µg/ml)
- Codeine, 10 mg, PO, TID INH: 1.18 PZA: 20.85 INH: 1.16 PZA: 15.97
- Albumin 500 mg, PO, TID RIF: 2.67 EMB: 1.23 RIF: 1.26 EMB: 1.16

2020.06.05 2020.07.26 2020.07.27

- Dx: Pulmonary TB - Last dose administration: - Last dose administration:

- Start of treatment: HRZE; PO; fasting state HRZE; PO; fasting state
HRZE, PO, QD (300/600/1600/1100 mg) (300/600/1600/1100 mg)
(300/600/1600/1100) - Time: 20:00 - Time: 20:00
- Fixed dose combination
 Laboratory Findings
Biochemistry Hematology
Name Normal Range 2020.07.24 Name Normal Range 2020.07.24
ALB 3.8-5.3 g/dL 3 WBC 4-10 x 109/L 8.6
TPRO 6.7-8.3 g/dL - RBC 4.2-6.3 x 1012/L -
AST 13-33 U/L 25 HGB 14-18 g/dL 10.7

SaturnALT 6-27
is a gas giant, 17 HCTDespite38-52 %
being red, -
Mars is cold place.
composed mostly of PLT 140-440 x 109/L 343
TBIL
hydrogen 0.2-1.2
and helium 0.59 It’s full of iron oxide
NEU dust
40-80 % 84.7
UA 3-5.5 mg/dL -
LYM 15-50 % 8.8
BUN 8-22 mg/dL 12
MON 2-11 % 4.6
CR 0.8-1.2 mg/dL 1.3
EOS 1-7 % 1.7
eGFR 62 mL/min/1.73 m2
BAS 0-1 % -
ANC ~ x 109/L
 Other Tests

PGX result
Chest X-ray
• NAT2: *6/*7;
Jupiter is aslow
ultra gas giant
• Samples: Sputum • Cavitary lung lesion
acetylator and the biggest
• Xpert: MTB (-) • Fibrosis infiltration
• SLCO1B1:planet
*1b/*1bin our
; Solar
System
normal transporter
function

2020.04.23 2020.07.24 2021.01.08

Pharmacokinetics Results (1st TDM)

LLoQ (µg/ml)
• EMB: 0.1
• INH: 0.2
• RIF: 0.4
• PZA: 2
Drug concentration
• All drug concentrations are within the reference range
Pharmacokinetics Results (2nd TDM)

LLoQ (µg/ml)
• EMB: 0.1
• INH: 0.2
• RIF: 0.4
• PZA: 2
Drug concentration
• All drug concentrations are within the reference range
 Scatter Plots of INH

All TDM Data Normalized to Standard Dose 300mg Same Dose 300 mg, QD
 Scatter Plots of RIF

All TDM Data Normalized to Standard Dose 600 mg Same Dose 600 mg, QD
 Scatter Plots of PZA

All TDM Data Normalized to Standard Dose 1500 mg Same Dose 1600 mg, QD
 Scatter Plots of EMB

All TDM Data Normalized to Standard Dose 800 mg Same Dose 1100 mg, QD
 Medical Issues and Suggestions

PK

- INH drug concentration within reference

range
- NAT2 *6/*7 (ultra slow acetylator) =>
increase OR of DILI to 4.23, compared to
*4/*4
=> Pay attention and regular check liver
function test

Suvichapanich et al., Pharmacogenet Genomics. 2018 Jul;28(7):167-176. PMID: 29781872

Case 3 (TB510086)
• Pulmonary TB
• INH BLLoQ; Long TAD
• Neuropathy Peripheral
• Low dosage of Anti-TB drugs
• M/36 y.o; 56 kg, 175 cm Diagnosis and Medication History
• Dx: Pulmonary TB;
Pulmonary TB; DS-TB
• Comorbidity: NA 2020.08.10
• Concomitant
- Last dose
medication : NA 2020.08.03
administration :
- ADR : Neuropathy RHZE; PO; fasting
Peripheral state(450/225/1200/8
25 mg)
- Time : 21.30

2020.07.27 2020.08.06 2020.08.11

- Dx : Pulmonary TB; DS- - Concomitant medication : 1st TDM
TB Pyridoxine 10 mg PO QD Time: 7.30; TAD: 10 hours
- Start of treatment : Drug concentration (µg/ml)
RHZE; PO; QD; FDC INH: 0.14
(450/225/1200/825 mg) RIF: 2.96
EMB: 1.04
PZA: 18.8
 Laboratory Findings
Biochemistry Hematology
Name Normal Range 2020.08.06 Name Normal Range 2020.08.06
ALB 3.8-5.3 g/dL 3.8 WBC 4-10 x 109/L 7.35
TPRO 6.7-8.3 g/dL - RBC 4.2-6.3 x 1012/L -
AST 13-33 U/L 31 HGB 14-18 g/dL 12.9

SaturnALT 6-27
is a gas giant, 32 HCTDespite38-52 %
being red, -
Mars is cold place.
composed mostly of PLT 140-440 x 109/L 325
TBIL
hydrogen 0.2-1.2
and helium 0.39 It’s full of iron oxide
NEU dust
40-80 % 72.1
UA 3-5.5 mg/dL -
LYM 15-50 % 17.4
BUN 8-22 mg/dL 8
MON 2-11 % 0.9
CR 0.8-1.2 mg/dL 0.6
EOS 1-7 % 0.5
eGFR 129.3 mL/min/1.73 m2
BAS 0-1 % -
ANC ~ x 109/L -
 Other Tests

PGX result
• AFB : No AFB seen • NAT2: *4(wt)/*5;
Jupiter is a gas giant
• Xpert: MTB (+) Intermediate and the biggest
acetylator
RIF resistant • SLCO1B1:planet
*1b/*1bin our
; Solar
(not detected) System
normal transporter
function

2020.07.27 2021.08.01
Pharmacokinetics Results

Drug concentration
• INH, RIF and EMB concentrations were within the
reference range, however the drug concentrations of
INH is 0.14 and considered as BLLoQ (LLoQ for
INH : 0.2)
 Scatter Plots of RIF

All TDM Data Normalized to Standard Dose 600 mg Same Dose 450 mg, QD
 Scatter Plots of EMB

All TDM Data Normalized to Standard Dose 800 mg Same Dose 825 mg, QD
 Scatter Plots of PZA

All TDM Data Normalized to Standard Dose 1500 mg Same Dose 1200 mg, QD
 Medical Issues and Suggestions

Medical Issue
PK • ADR : Peripheral Neuropathy
• INH concentration -> BLLoQ • Pyridoxine -> only 10 mg, It will be
(maybe because of long TAD :10 better to increase the dosage into 50
hours, INH T1/2 : 1.5 hours for fast mg*
acetylator and 4 hours for slow
acetylator)
• Long TAD -> we suggest the TAD
Body Intensive Phase Continuous
for next sampling time within 2-6 Weight RHZE (150/75/400/275) Phase
hours RH (150/150)
• Other reason : INH dosage in this
patient is lower (225 mg) compared 30-37 kg 2 tablets 2 tablets
to the dosage that usually given to 38-54 kg 3 tablets 3 tablets
his weight (300 mg).
55-70 kg 4 tablets 4 tablets
>70 5 tablets 5 tablets
*Mafukidze Arnold, et. al , Peripheral neuropathy in persons with tuberculosis. J.Clin Tuberc
other Mycobact Dis. 2016 Jan; 2: 5-11
Case 4 (TB510087)
• Pulmonary TB
• Multiple ADRs
• BLLoQ of INH and STR; Long TAD
• F/39 y.o; 50 kg, 158 cm
• Dx: Pulmonary TB; DS-TB
Diagnosis and Medication History
• Comorbidity: ITP (2019/11/22), 2020.05.26
DM(2020/02/22) 1st TDM
• ADR : Azotemia; Steven-Johnson Syndrome 2020.05.05 Time: 10.50 ; TAD:
• Concomitant medication : NA 2020.04.14 - Change regimen : 13.83 hours
INH/EMB/STR (750/750/750 mg) PO Drug concentration
- Dx : Pulmonary TB & IM for STR; QD (µg/ml)
- Start treatment : RHZE INH: <0 (BLLoQ)
(450/225/1200/825 mg); PO; QD -Co-med : Cetirizine 10 mg PO BID;
Dexamethasone 5 mg IV BID; STR : 0.29 (BLLoQ)
- Co-med : Codein 10 mg PO TID
- Paracetamol 500 mg PO TID Diphenhydramine 10 mg IV BID EMB : 0.50

2019/11/22 & 2020/02/22 2020.05.04 2020.05.25

- Diagnosed by : Idiopathic ADR : Azotemia (PZA) & - Last dose administration
Thrombocytopenic Allergic Reaction (RIF) -> HES; PO & IM ; fasting
Purpura (2019/11/22); SJS state
DM (2020/02/22) (750/750/750 mg)
Stop PZA and RIF - Time: 21:00
 Laboratory Findings
Biochemistry Hematology
Name Normal Range 2020.04.30 Name Normal Range 2020.04.30
ALB 3.8-5.3 g/dL 3.6 WBC 4-10. x 109/L 10.17
TPRO 6.7-8.3 g/dL - RBC 4.5-6.3 x 1012/L -
AST 13-33 U/L 34 HGB 14-18 g/dL 12.2

SaturnALT 6-27
is a gas giant, 31 HCTDespite38-52
being %
red, -
Mars is cold place.
composed mostly of PLTIt’s full 140-440 x 109/L 142
TBIL
hydrogen 0.2-1.2
and helium 0.67 of iron oxide
NEU dust %
40-80 90.7
UA 3-5.5 mg/dL -
LYM 15-50 % 6
BUN 8-22 mg/dL 35
MON 2-11 % 3.2
CR 0.8-1.2 mg/dL 2.8
EOS 1-7 % 0.6
eGFR 20.4 mL/min/1.73 m2
BAS 0-1 % -
ANC ~ x 109/L -
 Other Tests

PGX result
• AFB : Few (+2) Chest X-ray
• NAT2: *4(wt)/*4(wt);
Jupiter is a gas giant
• Xpert: MTB (+) • Mild Lung damage
and the biggest
rapid acetylator
RIF resistant • Fibrosis Infiltrate
• SLCO1B1:planet
*1a/*15in our
; Solar
(not detected) • Conclusion : Lung TB
System
intermediate transporter
function

2020.04.11 2020.04.14 2021.01.08

Pharmacokinetics Results

Drug concentration
• EMB concentration was within the reference range,
however the drug concentrations of INH is <0 and STR
is 0.29, both are considered as BLLoQ (LLoQ for
INH : 0.2, STR : 1 µg/ml)
 Scatter Plots of EMB

All TDM Data Normalized to Standard Dose 800 mg Same Dose 750 mg, QD
 Medical Issues and Suggestions

Unusual data and Medical

BLLoQ Issue
• INH and STR concentration ->
BLLoQ • Dosage of Isoniazid seems too high
• This might be because Long TAD for this patient with DS-TB
-> 13,83 and also the NAT2 -> confirmed to CRC
phenotype of the patient is rapid • Multiple ADRs -> one of them is
acetylator Azotemia -> pay attention for
• T1/2 of isoniazid is 1.5 hours for ethambutol side effects
fast acetylator and 4 hours for slow
acetylator, T1/2 of Streptomycin is
3 hours.*
• We suggest the TAD for next
sampling time within 2-6 hours

* Alsultan, A. and C.A. Peloquin, Therapeutic drug monitoring in the treatment of tuberculosis: an update.
Drugs, 2014. 74(8): p. 839-54.
Thank you for your attention!