University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

JWC Alffenaar 1 ‡, M van der Meer 1, JGW Kosterink 1, D van Soolingen 2, TS van der Werf 3, R van Altena 3

1 Depart of Clinical and Hospital Pharmacy, UMCG, 2 National Mycobacteria Reference Laboratory, RIVM, 3 Department of Pulmonary Diseases and Tuberculosis, UMCG

AMIKACIN CUMULATIVE DOSE PREDICTS HEARING LOSS IN MDR‐TB PATIENTS

‡The training in Clinical Pharmacology was financially supported by the Dutch Society for Clinical Pharmacology and Biopharmacy

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Amikacin – Tuberculosis• WHO: group 2 drug (injectables)• Need for optimizing Tuberculosis (TB) treatment

– Oto‐vestibulo‐toxicity: Dizziness, Hearing loss– Nephrotoxicity – Adverse effects: prolonged treatment, higherdosage

• ATS schedule [1]

– 15 mg/kg/day, max of 1000 mg/day– Age > 50yrs, 10mg/kg/day

1ATS. Am J Respir Crit Care Med 2003

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Toxicity: Fixed dose regimen• TB or NTM patients (n=87) randomized

– 15 mg/kg 5 times per week

– 25 mg/kg 3 times per week

– streptomycin, kanamycin, or amikacin (IV) 

• Hearing loss

– found in 32/87 (37%) of the patients• older age

• larger cumulative dose

• Cmax:

– > 40 mg/L

Peloquin et al CID 2004

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

5X 15 versus 3X 25 mg/kg weekly ‐ toxicity

Peloquin et al CID 2004

kanamycin and amikacin: equal ototoxicity with equal cumulative dosage

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Amikacin 

• MDR‐TB; DST by RIVM

• Dose: 400‐700mg qd; after 6 months thrice weekly

• TDM (local protocol)

– Correlation between plasma concentrations 

•Efficacy: Cmax/MIC ratio > 10

•Prevention of resistance Cmax/MIC ratio > 20‐25

•Toxicity: Cmin > 3 mg/L

TB Center Beatrixoord

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Hypothesis

• Is toxicity determined by AMK peak concentration?

• Is the lower dose sufficient for adequate PK/PD

• Objective:– To evaluate hearing loss of TDM guided dosing of AMK in TB patients in our Center

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Methods• Retrospective single centre study• Inclusion criteria:

– all patients consecutively admitted to BO/UMCG TB Unit between 1998‐2008

– > 3 days on AMK – peak and trough level at steady state 

• Analytical methods– samples determined by fluorescence polarization immunoassay (TDx, Abbott) 

• Drug susceptibility – Middlebrook 7H10 agar dilution method (RIVM)

• Audiogram – audiometry at 250, 500, 1000, 2000, 4000 and 8000 Hz 

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Patients characteristics

9 (14,8%)11 (18,0%)29 (47,5%)

• Alcohol• Drugs• Smoking

Intoxication

7 (9.7%)5 (6.9%)4 (5,5%)3 (4,2%)3 (4,2%)

• HIV• DMII• Hepatitis B• Malaria• Other

Co‐morbidities

9 (12.5%)29 (40.3%)7 (9.7%)

19 (26.4%)3 (4.2%)5 (6.9%)

• European• Sub‐Sahara African• Mediterranean• Asian• S‐American• Other

Ethnicity

52/20 35.5 (27‐47.3) 

60.7 (50.0 – 69.4)

• Gender (M/F) • Age (years)• Weight (kg)

(n=72)General

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Results: Cmax

8.8 (IQR; 7.0 ‐ 10) 

24.5 (IQR; 20.6 ‐ 28.3)

Male (n=52)

0.02128.9 (IQR; 23.9 ‐ 33.8)25.5 (IQR; 20.8 ‐ 30.0)Cmax (mg/L)

Dose (mg/kg)

Cmax

8.1 (IQR; 6.8 ‐ 8.7)

Female (n=20)

0.238.5 (IQR; 7.0 ‐ 10.0)

P(n = 72)

• Cmax correlation with:• mg/kg total body weight: R 0.27 (P = 0.022) • mg/kg ideal body weight: R 0.47 (P < 0.005)

• PD• mean MIC value 2.0 (range 0.25 – 5.0) mg/L• mean Cmax/MIC ratio 26.3 (range 3‐104)

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Results: critical value?

Treatment duration (days)

0 100 200 300 400 500

Hea

ring

loss

0

1

Cumulative dose (mg)

0 50x103 100x103 150x103 200x103 250x103

Hea

ring

loss

0,0

1,0

Cumulative dose (mg) Treatment duration (days)

yes

no

Hea

ring

loss

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Results: adverse events

0.1737 (22 ‐ 62)33 (13 ‐ 74)age

0.015187 (6 ‐ 473)93 (3 ‐ 453)treatment (days)

Cmax

cumulative dose (mg)

Hearing loss 18 %

25.6 (19.3 ‐ 35.0)

50826 (1200 ‐ 181857)

YES 

(n = 13)

0.925.7 (7.9 – 43.0)

0.02340488 (5400 ‐ 64528)

PNO

(n = 59)

• Renal function – Cmin < 3 mg/L in all but one patients (6.8 mg/L)– 77% no increase in serum creatinine– 23% increase in serum creatinine (due to increase in body mass)

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Discussion• Hearing loss

– cumulative dose– treatment duration

• Treatment duration decisions were based on– bacterial load– co‐medication– adverse effects

• TDM – women had higher Cmax than men

• Vd of AMK is determined by body water not body fat

– data suggest that dosing should be based on IBW – not TBW

18% vs 37% hearing loss

8.5 (IQR; 7.0 ‐ 10.0) vs 15 mg/kg

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Discussion (I)

55.3 (1.2‐227)53.2 (8–191)Cumulative dose (g)

18%18%Ototoxicity

400‐700750‐1000Dose (mg)

35.5 (27‐47.3)35.7 (10‐83)Age (years)

52/20 81/29Gender (M/F) 

1.4%7.5%Renal toxicity

cohort1998-2008

cohort1995-2000[1]

TB Center Beatrixoord

[1] De Jager et al IJLTD 2002

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

• Amikacin variability in PK/PD– Dose in mg/kg IBW explains only 22% of the variability! 

– Burn patients[1]:• Cmax correlated with % of body surface area affected

– Neutropenic patients[2]:• correlated with creatinine clearance

1Conil et al Int J Antimicrob Agents. 20062Tod et al AAC. 1998

Discussion (II)

WHO dose of 15 mg/kg based on historical conventions, not on EBM criteria

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Conclusion• Lower dose in mg/kg IBW qd is possible

– Reduction of cumulative dose!• Peak level recommended to assure Cmax/MIC ratio• Hearing loss

– related to cumulative dose – not related to peak concentration

• Trough level superfluous if renal function OK 

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

• Future studies– determine Mutant Prevention Concentration (MPC) of M tuberculosis and relation of MIC to MPC 

– prospective PK study to develop dosing algorithm – prospective randomised clinical trial 

• ATS/WHO dosage vs concentration‐guided dosing– third arm; anti‐oxidants?? 

• clinical endpoint: – Primary end‐point: toxicity

» reduction of hearing loss of 50% (40=>20%) – Secondary end‐point: efficacy

» Cmax/MIC ratio = 25• setting “highly endemic region” or EUR (TB‐NET)

Future perspectives

University Medical Center Groningen Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston

Thank you for your attention!

Presented at the 3rd Intl. Workshop on Clinical Pharmacology of TB Drugs11 September 2010, USA Boston