Dose Individualization in HIV Therapy

Courtney V. Fletcher, Pharm.D.Dean, College of Pharmacy

Professor, Department of Pharmacy Practice and Division of Infectious Diseases

University of Nebraska Medical Center

Response Rates of Patients to a Major Drug for Selected Therapeutic Areas

Therapeutic Area Efficacy Rate (%)Alzheimer’s 30Analgesics (Cox-2) 80Asthma 60Cardiac Arrhythmias 60Depression (SSRI) 62Diabetes 57Incontinence 40Migraine (acute) 52Oncology 25Osteoporosis 48Osteoporosis 48Rheumatoid arthritis 50Schizophrenia 60

Spear BB, et a. Trends Mol Med 2001;7:201-4

The Sources of Variability in Response

Blaschke T, et al. Annu Rev Pharmacol Toxicol 2012;52:275-301.

Concentration-Controlled Combination Antiretroviral Therapy (GCRC # 540)

RANDOMIZE

Controlled Therapy• ZDV, Css ≥ 0.17 mg/L• 3TC, Css ≥ 0.40 mg/L • IDV, Cmin ≥ 0.13 mg/L

Standard Therapy• ZDV, 600 mg/day• 3TC, 300 mg/day• IDV, 2400 mg/day

6 months of therapy; participants with plasma HIV RNA < 200 copies/mL can continue therapy for 6 more months

OR

ZDV, 3TC, and IDV Concentrations

0.1

0.15

0.2

0.25

0.3

0.35

Zido

vudi

ne C

ss (m

g/L)

Conventional Concentration-Controlled

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Lam

ivud

ine

Cs

s (mg/

L)

Conventional Concentration-Controlled

0

0.1

0.2

0.3

0.4

0.5

Indi

navi

r Cm

in (m

g/L)

Concentration-ControlledConventional

* Fletcher CV, Anderson PL, Kakuda TN, et al. AIDS 2002;16:551-60

Drug Standard Concentration Controlled

Zidovudine 9/17 (53%) 16/16 (100%) *

Lamivudine 11/17 (65%) 16/16 (100%) *

Indinavir 3/17 (18%) 14/16 (88%) *

* p<0.05

Percent with Undetectable HIV RNA

*

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Per

cent

with

Und

etec

tabl

e H

IV R

NA

Week of Therapy

Concentration-ControlledConventional

* Fletcher CV, Anderson PL, Kakuda TN, et al. AIDS 2002;16:551-60

Pharmacokinetic VariabilityWhat Do We Need to Know

How much is expected? Interpatient Intrapatient

How much is too much? Exposure-response relationships

Can we control for, or accommodate the effects of pharmacokinetic variability? Adherence Pharmacokinetic strategies Pharmacodynamic strategies

Dose Optimization and Individualization

Questions Is there a role for dose individualization? Is there a role for age-specific dosing? Is there a role for pharmacogenomics? Is there a role for compartment/tissue targeted

dosing?

Predictive Value of EFV Concentrations for Viral Suppression and CNS Adverse Effects

Viralsuppression

CNSadverseeffects

Optimal range

Plasma Efavirenz (ng/mL)100001000100

0

60

80

100

40

20

Pro

babi

lity

(%)

Marzolini C, et al. AIDS 2001;15:71-75.

Efavirenz Population Pharmacokinetics

0

2000

4000

6000

8000

10000

12000

14000

16000

0 5 10 15 20 25 30 35 40 45

DV

PREDEFV

(ng/

mL)

Hours Post Dose

Pharmacokinetics, Dynamics, and Adherence

Brundage RC…Fletcher CV. Antimicrob Agents Chemo 2004;48:979-84

Subjects Sorted by Ascending Integrated PK and Adherence Measure (IPAM)

-1

-0.5

0

0.5

1

1.5

2

LOG

(Cpr

ed/C

obs)

Cobs < 40% Cpred

Cobs > 40% Cpred

0 0.2 0.4 0.6 0.8 1.0

Brundage RC…Fletcher CV. Antimicrob Agents Chemo 2004;48:979-84

Time to Failure (HIV-RNA > 400) vs. Adherence Score

Brundage RC…Fletcher CV. Antimicrob Agents Chemo 2004;48:979-84

0

.2

.4

.6

.8

1

Pro

porti

on N

ot F

aile

d

0 8 16 24 32 40 48

Time (weeks)

Low Adherence

High Adherence

n fail rate31 7 23%19 10 53%p<0.003

PK/PD of Dolutegravir

Min S, et al. AIDS 2011;25:1737-45.

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

Placebo2mg QD10mg QD50mg QDModel Fit, Emax= -2.6, EC50= 0.036μg/mL

Day

11

log 1

0VL

Cha

nge

from

Bas

elin

e

Maximum Effect (Emax) Model of DolutegravirExposure vs. Response

Ctrough (μg/mL)

Dose Optimization and Individualization

Questions Is there a role for dose individualization? Is there a role for age-specific dosing? Is there a role for pharmacogenomics? Is there a role for compartment/tissue targeted

dosing?

TFV Plasma and Intracellular Kinetics-Dynamics in Children & Adolescents

Tenofovir disoproxil fumarate (TDF) Safe and effective; widely used for treatment of HIV-infection, Limited plasma and intracellular PK data in children.

TFV plasma and intracellular TFV-DP PK were quantified in 47 HIV-infected children and adolescents (8.6-25 yrs).

These data were pooled with those of 55 HIV-infected adults (25-60 yrs).

Non-linear mixed effects modeling was used to describe the PK and explore the influence of covariates (e.g. age, renal function).

An indirect, stimulation of response model was used to describe the formation of TFV-DP.

Baheti G, King J, Acosta E, Fletcher CV. AIDS 2013;27:221-5.

TFV Concentrations and Oral Clearance by Age Group

0

0.5

1

1.5

2

<12 12-<17 17-<25 >25

Age (years)

TFV

CL

(L/h

/kg)

0

50

100

150

200

250

300

350

400

0 5 10 15 20 25

TFV

Con

cent

ratio

ns (n

g/m

L)

Time (Hour)

Age <25 yrs

Age >25 yrs

Baheti G, King J, Acosta E, Fletcher CV. AIDS 2013;27:221-5.

Mean Plasma TFV and Intracellular TFV-DP Concentrations by Age Group

0

50

100

150

200

250

300

350

400

0 5 10 15 20 25

TFV

Con

cent

ratio

ns (n

g/m

L)

Time (Hour)

Age <25 yrs

Age >25 yrs

0

20

40

60

80

100

120

140

160

180

200

0 5 10 15 20 25

Age <25 yrs Age >25 yrs

TFV-

DP

(fmol

/106

cel

ls)

Baheti G, King J, Acosta E, Fletcher CV. AIDS 2013;27:221-5.

Differences in Children-Adolescent and Adult Plasma and IC TFV Kinetics

Parameter > 25 years < 25 years

N and Age (median) N=102 subjects; 21 years (range, 9 to 60 years)

PLASMAPlasma CL/F (L/h) 42.3 57.6

INTRACELLULARKin (h‐1) 0.21

EC50 (ng/mL) 116 69

Kout (h‐1) 0.0081 0.0099

Intracellular T1/2 (h) 86 70

Emax (fmol/106) 1200

Children and adolescents achieved higher TFV-DP concentrations despite lower plasma exposure.

An increased sensitivity to phosphorylation is suggested as a mechanism based on a lower EC50.

Dose Optimization and Individualization

Questions Is there a role for dose individualization? Is there a role for age-specific dosing? Is there a role for pharmacogenomics? Is there a role for compartment/tissue targeted

dosing?

Isoniazid (INH)

Used for the treatment and prevention of TB for over 50 years.

In adults, INH chemoprophylaxis has been associated with a marked reduction in the risk of TB disease.1

INH is the only agent recommended for TB prophylaxis in children.2,3

The WHO recommended dose for children is 5 mg/kg/day. 10 mg/kg/day was effective at preventing TB in a recently

published study in 263 HIV-infected older children.4

There are no data on the PK of INH in infants, the appropriate dose of INH in infants, or INH PK from administration of a crushed tablet.

1Hsu KHK, Starke JR. Pediatr Infect Dis 1993; 4:283-90, 2RedBook 2003, 26th edition, American Academy of Pediatrics 2003:642-60, 3Centers for Disease Control and Prevention. MMWR 2000;49:1-51, 4Zar HJ, et al. BMJ 2007;334:136-148

INH PK and PG Objectives Characterize INH PK in infants randomized at 91-120

days of life to INH 10–20 mg/kg/d orally QD or placebo (enrolled in P1041) using population PK techniques.

Determine N-acetyltransferase-2 (NAT2) genotype and evaluate if acetylator genetics explains INH PK, and if there is a concordance between NAT2 genotype and acetylator phenotype (INH CL/F) in infants.

Evaluate the effects of other covariates, such as HIV infection, sex and body weight on INH PK.

Develop a enzyme maturation PK model that can separate the effects of (1) body size, (2) enzyme maturation and genotype, and (3) bioavailability on INH PK.

INH Concentration-Time Data

Kiser JJ, Zhu R, D’Argenio DZ …Fletcher CV. Ther Drug Monitoring 2012; 34(4):446-51.

INH Enzyme Maturation Model

Zhu R . . . D’Argenio DZ, Fletcher CV. J Clin Pharmacol 2012; 52(4):511-9

INH PK in Children

INH CL/F was dependent NAT2 genotype, with a concordance observed between NAT2 genotype and acetylator phenotype (INH CL/F).

A different NAT2 enzyme maturation pattern was found for each of the three acetylation groups: Fast: 14.25 L/h at 3 mo to 22.84 L/h at 24 mo; Intermediate: 10.88 L/h at 3 mo to 15.58 L/h at 24 mo. Slow: flat at 7.35 L/h at 3 mo to 24 mo.

INH CL was also dependent upon age and body weight. INH relative bioavailability increased from 0.72 at 3 mo

to 0.95 at 24 mo. The dose of 10-20 mg/kg (avg 14.5 ± 2.8) was safe

and well tolerated, and PK was similar to data in older (median 3.8 y) children and adults.

Simulations of INH Cmax(INH Dose of 14.5 mg/kg/d)

Cmax (mg/L)

3month 24 month 48 month

SS FS FF SS  FS FF SS FS FF

95th 15.19 13.56 12.46 21.31 17.01 14.85 22.22 17.01 15.38

75th 10.74 9.49 8.65 15.00 11.84 10.27 15.62 11.82 10.64

Median 8.84 7.82 7.11 12.36 9.75 8.42 12.87 9.72 8.72

25th 7.01 6.18 5.62 9.81 7.70 6.64 10.22 7.68 6.88

5th 7.01 6.18 5.62 9.81 7.70 6.64 10.22 7.68 6.88

Cmax < 3 mg/L 0 0.2% 0.8% 0 0 0 0 0 0

Kiser JJ, Zhu R, D’Argenio DZ …Fletcher CV. Ther Drug Monitoring 2012; 34(4):446-51.

Dose Optimization and Individualization

Questions Is there a role for dose individualization? Is there a role for age-specific dosing? Is there a role for pharmacogenomics? Is there a role for compartment/tissue targeted

dosing?

Distribution of the PI, DPC681 + RTV

QWBA demonstrated lowest distribution in the brain and highest in the liver. Differential distribution in brain with CNS < CSF.

Solon EG et al. Drug Metab Dispos 2002;30:1164.

TFV Tissue Kinetics in Rats by PET

TFV tissue kinetics evaluated with an fluorine-18 radiolabeled analog Lowest distribution: brain, mesenteric LN and testes Similar or equivalent distribution: colon and jejunum

Di Mascio M, et al. Antimicrob Agents Chemother 2009;53:4086-95

Viral Sanctuaries during HAART in a Non-Human Primate Model for AIDS

Rhesus macaques treated with TDF, FTC, EFV.

Plasma viral load at necropsy ranged from 11-28 copies/mL.

vDNA and vRNA were detected during HAART from numerous anatomical compartments.

The highest levels of vDNA and vRNA were in lymphoid tissues: spleen, lymph nodes and GI tract tissues.

North TW . . Luciw P. J Virol 2010;84:2913.

Drug Absorption via Intestinal Lymphatic System

Physicochemical Properties Associated with Lymphatic System Absorption Molecular weight Particle size

Trevaskis N, et al. Adv Drug Deliv Rev 2008;60:702-16.

Log P (octanol:water partition) Long chain TG solubility

Preclinical PK of Nanoformulated ATV/RTV

Gautam N et al. Antimicrob Agents Chemother 2013; 57:3110-20.

Lymph Node Targeting with a Three Drug anti-HIV Lipid Nanoparticle (LNP)

LopinavirLNP/freeratio

RitonavirLNP/free ratio

TenofovirLNP/free ratio

Plasma AUC 18.2 14.0 7.0

Intracellular peripheral MNCs 20.4 >400 70.0

Intracellular LN MNCs >485 50.5 0.7

Freeling JP…Ho RJY. AIDS 2014,28:2625-27.

Tissue Distribution of TFV after Oral TDF or Tenofovir Alafenamide (TAF, GS 7340)*Tissue or Fluid TDF

concTAFconc

TAF:TDF

Kidney 88 80 0.9

Lungs 0.50 4.34 8.2

Inguinal lymphnodes

0.28 4.12 15

Spleen 0.63 8.13 12.8

Brain < LOD < LOD ‐

Ileum 0.50 4.61 9.2

Prostate 0.24 2.14 9.1

Bone marrow 0.20 2.05 10.2

* Male beagle dogs. Lee, W.A. et al. Antimicrob Agents Chemo 2005;49:1898.

Dose Optimization and Individualization in HIV Therapy

Questions and Answers Is there a role for dose individualization?

» Yes, because variability in exposure contributes to variability in response.

Is there a role for age-specific dosing? » Yes, because age-related changes in PK and PD

may contribute to differences in responses. Is there a role for pharmacogenomics?

» Yes, because genetic-related variability in PKPD contributes to variability in response.

Is there a role for compartment/tissue targeted dosing?» Probably, to achieve effective concentrations in

protected or reservoir sites.

In short, after all this discussion, the only principle of drug dosage which survives is that the dose must be adjusted to the individual patient.

Dawson WT. Ann Intern Med 1940;13:1594-1613