TDM of HIV

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TDM of HIV

• Winter 2003

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Goals for today

• What am I mixing?
• Why am I mixing?
• What is my goal?
• What should I expect to happen when mixing?

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DRUG INTERACTIONSAND HIV PHARMACOLOGY

• OUTLINE
• What is the ideal dual PI combination?
• How important is the Cmin/IC50 ratio?
• Can dual PIs be given once-a-day?
• What about dual PIs and drug toxicity?
• Anything else we need to worry about?

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DRUG INTERACTIONSAND HIV PHARMACOLOGY

• CONTROVERSY
• What is a therapeutic blood level for any
  antiretroviral drug?
• In general, higher trough is better!
• But, we still dont know the right answer!
• Should therapeutic drug monitoring be used to
  individualize therapy and improve outcomes?
• May not be needed with optimal PK profiles!

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Basic Pharmacology Principles
Cmax
Drug Level
Area Under the Curve (AUC)
Cmin
PK Benefit
IC90
Area of Potential Replication
IC50
Dosing Interval
Time
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BENEFICIAL DRUG INTERACTIONS

• Ritonavir-Saquinavir
• Ritonavir-Indinavir
• Delavirdine-Saquinavir
• Ritonavir-Nelfinavir
• Nelfinavir-Saquinavir
• Ritonavir-Lopinavir (Kaletra)
• Ritonavir-Amprenavir

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QD vs. BID Kaletra?

• Comparison of once-daily versus twice-daily
  Kaletra (lopinavir/ritonavir)
• Objective To investigate the safety, efficacy,
  and pharmacokinetics of QD and BID
  lopinavir/ritonavir (LPV/r) regimens

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QD vs. BID Kaletra?

• Results (cont)

Lopinavir Pharmacokinetics and Pharmacodynamics
QD (800/200 mg) vs. BID (400/100
mg) N 17 19 CMAX 10.94 9.81 C
MIN 2.46 5.51 CTROUGH
3.62 7.13
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LPV/r QD Data (Study 056)
LPV/RTV 800/200 mg QD (n19) LPV/RTV 400/100 mg
BID (n19)
IQ84
IQ40

• Pharmacokinetic analysis of 38 ARV-naïve patients
  with HIV RNA gt50 copies/mL
• LPV/RTV 800/200 mg QD (n19) vs LPV/RTV 400/100
  mg BID (n19), both d4T/3TC

Bertz R et al. 9th CROI, Seattle, 2002, 126
IQ Ctrough/IC50
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BENEFICIAL DRUG INTERACTIONS

• Cmin/IC50 Ratios
• Drug concentrations are an important determinant
  of the success or failure of an antiretroviral
  regimen.
• One way to indicate a drugs potency is to use
  the inhibitory quotient (I.Q.), or Cmin/IC50
  ratio.
• A high I.Q. (large ratio of Cmin to IC50) is an
  important target for emerging anti-HIV drugs.
• A low I.Q. (small ratio of Cmin to IC50) may be
  associated with less suppression of HIV
  replication, increased risk of resistance, and
  more dire consequences of non-adherence.

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Basic Pharmacology Principles
Cmax
Drug Level
Area Under the Curve (AUC)
Cmin
PK Benefit
IC90
Area of Potential Replication
IC50
Dosing Interval
Time
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Definition of Inhibitory Quotient
Cmin   IQ ___________________________
_______ (IC50 or IC95) X
(Protein Binding Adjustment)
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CminIC50

• Cmin
• pharmacokinetic parameter most closely associated
  with antiviral effect
• low levels of Cmin have been correlated with
  virological failure
• improved with ritonavir-enhanced regimens and,
  to some degree, with delavirdine

• IC50
• concentration of drug required to inhibit
  
  50 growth of virus
• growth of virus is impacted by
• the number of mutations
• the specific mutations (resistance profile)

Burger DM, et al. 37th ICAAC, 1997 Abs
A-19. Acosta EP, et al. 37th ICAAC,1997 Abs
A-15.
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Defining Inhibitory Levels

• IC50 the concentration needed to inhibit
  replication by 50 in vitromore consistent
  measure
• IC95 the concentration needed to inhibit
  replication by 95 in vitro
• EC50 the effective concentration needed to
  inhibit replication by 50 in vivo
• ED95 the effective dosage needed to inhibit
  replication by 95 in vivo

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ONCE-A-DAY DUAL PIS?

• Dual PIs that might be given once-a-day
• Ritonavir-Amprenavir
• Ritonavir-Lopinavir (ABT378)
• Ritonavir-Indinavir
• Ritonavir-Saquinavir
• Others
• All investigational

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Pharmacokinetics of Amprenavir and
Amprenavir/Ritonavir
APV600/RTV100 BID
Mean IC50 of APV against HIV of HAART-naïve
patients
Mean IC50 of APV against HIV of multi-PI-failure
patients
Sadler BM, et al. 7th CROI, 2000 Abs 77.
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DUAL PI/NNRTI COMBINATIONS

• Importance of the RTV Dose
• Efavirenz decreased the indinavir AUC by 30 when
  added to IDV/RTV 800/100 mg BID.
• Efavirenz decreased the lopinavir AUC by 19, and
  decreased Cmin by 33 when added to standard dose
  Kaletra (400/100 mg BID).
• The RTV dose should be increased to 200 mg BID in
  dual PI combos with EFV or NVP.
• Kaletra should be increased to four capsules BID
  (533/133 mg BID) when combined with EFV or NVP.

40th ICAAC, 2000.
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Once-a-day Dosing Of Anti-HIV Drugs

• The Positives
• Q.D. dosing is more convenient than B.I.D. dosing
  
• Q.D. dosing may promote better overall adherence
  (i.e., a higher per cent of prescribed doses are
  taken)
• Q.D. drugs could be administered as directly
  observed therapy (DOT)

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Once-a-day Dosing Of Anti-HIV Drugs

• The Negatives
• Q.D. dosing generally produces a lower trough
  concentration (lower I.Q.) than B.I.D. dosing of
  the same drug
• The consequences of missing a dose may be worse
  for a Q.D. regimen than for a B.I.D. regimen
• The consequences of taking a dose late may be
  worse for a Q.D. regimen than for a B.I.D.
  regimen
• The risk of treatment failure/resistance may be
  higher for a Q.D. regimen than for a B.I.D.
  regimen

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INDINAVIR DOSE, CONCENTRATION, AND NEPHROTOXICITY

• Higher AUC and Cmax were associated with IDV
  nephrotoxicity in patients taking 800 mg q8h
  Burger et al., CROI 2001
• IDV Cmin was not associated with nephrotoxicity
• Increasing IDV Cmax and Cmin were associated with
  an increase in nephrolithiasis in patients taking
  IDV/RTV (400/100, 400/400, 600/100, or 800/100 mg
  BID 0, 2, 6, or 10) Lamotte et al., CROI
  2001
• Higher concentrations of IDV produced by RTV may
  increase the risk of nephrotoxicity in some
  regimens

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NON-PHARMACEUTCIALS ANDDRUG INTERACTIONS

• Garlic capsules for 19 days decreased the mean
  saquinavir AUC by 51, Cmax by 49, and trough by
  54 (Piscitelli et al., CROI 2001)
• Suggests interference with SQV bioavailability
• Smoking 4 THC cigarettes TID for 21 days
  decreased the mean nelfinavir AUC by 17, and the
  indinavir Cmax by 21 (Kosel et al., CROI 2001)
• Clinical significance and mechanism unknown.

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DRUG INTERACTIONS AND HIV PHARMACOLOGY

• SUMMARY
• Beneficial pharmacokinetic drug interactions can
  have a favorable impact on ART, but higher drug
  concentrations may produce more toxicity.
• The PK profile of some dual PI regimens supports
  further investigation of QD administration.
• The RTV dose may need to be gt100 mg BID in
  patients on dual PIs who also take an NNRTI.
• Dietary supplements and drugs of abuse may be
  potential sources of undesirable drug
  interactions.

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Goals for today

• What am I mixing?
• Primarily protease inhibitors
• Sometimes in conjunction with non-nucleoside
  reverse transcriptase inhbitors
• Why am I mixing?
• To improve outcomes via (hopefully)
• Enhanced adherence
• Improved IQs
• What is my goal?
• Maximal and durable suppression of HIV
  replication
• What should I expect to happen when mixing?
• Adverse events primarily associated with troughs