THE USE OF THERAPEUTIC DRUG MONITORING (TDM) IN
                                                         SF Forsyth1, P French1, E Macfarlane1, SE Gibbons2
          Camden     NHS
Primary Care Trust                                           1
                                                               Mortimer Market Centre, London                                                                                                                                                     UCL
                                                Department of Pharmacology, University of Liverpool, Liverpool

Introduction                                                                                                      Results
• Toxicity is a major reason for switching both    1st
                                                 and          2nd
                                                         line HAART                  regimes1
  and many side effects are related to high plasma drug levels.                                               Patient                                      Drug         Original Dose Original Trough               Post-adjustment Post-adjustment
                                                                                                                                                                                       Level xMEC†                       Dose      Trough Level xMEC†
• Evidence suggests that treatment failure is associated with low plasma levels
                                                                                                                       1                                    NFV           1250 mg bd               8.5               1000 mg bd                     3
  of PI’s (protease inhibitors) and efavirenz and TDM is often requested in this
  situation.                                                                                                           2                                    NFV           1250 mg bd               3.3               1000 mg bd                     3.2
                                                                                                                       3                        IDV/RTV 800/100 mg bd                               11              600/100 mg bd             not done
• With the more widespread use of boosted PI regimes and complicated drug
  interactions, however, high plasma drug levels are likely to become more of a                                        4                            IDV/RTV 800/100 mg bd                          8.8              600/100 mg bd             not done
  problem.                                                                                                             5                       APV/RTV 750/100 mg bd                               8.3              600/100 mg bd                   4.9
• BHIVA guidelines suggest that TDM may be useful in guiding dose                                                      6                    LPV/RTV 400/100 mg bd                             *1123 ng/ml           *266/100 mg bd          *9110 ng/ml
  modification where drug toxicity is suspected and thus preventing                                           †
                                                                                                                       MEC - minimum effective concentration
  discontinuation of an otherwise efficacious drug regimen.                                                   *        Normal range of values for LPV trough found in formal pharmacokinetic studies is 5500 ± 4000 ng/ml

                                                                                                                  • All patients noticed considerable improvement in their symptoms after dose
                                                                                                                  • Patients 1-5 had undetectable viral loads prior to dose adjustment and they
Aim                                                                                                                 have all maintained these levels of suppression to date.

• The aim of this study was to determine whether TDM and subsequent dose                                          • Patient 6 had failed to achieve an undetectable viral load prior to dose reduction
  modification was being used in the management of patients with suspected                                          and continues to have difficulties with adherence and resistance.
  drug toxicity at our centre.

                                                                                                                  • In our experience TDM can be used to reduce the risk of HIV treatment
Methods                                                                                                             intolerance and discontinuation.
• Of the 78 requests for TDM at our centre in 2001,16 were for suspected drug                                     • Toxicity from HAART threatens the sustained success of HIV treatment hence
  toxicity.                                                                                                         it is vital to minimize this risk.
• Following case note review, it was discovered that in 6 of these cases high                                     • PI’s are good candidates for TDM as they show high inter-patient variability
  drug levels were found and dose adjustment led to improvement of                                                  (Figure 1) and low intra-patient variability.
                                                                                                                  • There is evidence that TDM and dose adjustment reduces IDV nephrotoxicity2
                                                                                                                    and that plasma levels of efavirenz3 and RTV4 correlate with side effects but
                                                                                                                    there are no formal guidelines for the use of TDM in this situation.
Case Reports
                                                                                                                  • We recommend that clinicians consider using TDM for identifying possible drug
   Patients 1 and 2
                                                                                                                    toxicity before switching regime or even to prevent long term toxicity before it
   Patient 1 had been on nelfinavir (NFV) 1250 mg bd for 2 months when he                                           develops.
   developed diarrhoea, vomiting and weight loss.
                                                                                                                           Protease inhibitor trough plasma concentrations from adult patients on twice
   Patient 2 had had persistent diarrhoea since commencing NFV 3 years                                                     daily regimen analysed by the Liverpool TDM Service (data to January 2002)
   previously and all investigations including colonoscopy had been normal.                                                                                           The lines indicated the target minimum effective concentrations
                                                                                                                                                               (APV 350 ng/ml; IDV 120 ng/ml; LPV 75 ng/ml, RTV 2100 ng/ml; SQV 200 ng/ml)
   Microsporidium found in the stool had been treated with no change in
   symptoms.                                                                                                                                                                                                                              Alone
                                                                                                                                                                                                                                          + RTV
                                                                                                                                                                                                                                          + LPV

   Patients 3 and 4
                                                                                                                            Plasma Concentration (ng/ml)


   Patient 3 had been on indinavir (IDV) 800 mg tds for 7 years but switched to
   IDV 800 mg bd plus ritonavir (RTV) 100 mg bd for convenience. 2 months
   later he complained of pruritus and dry lips and skin. Pruritus screen (liver,                                                                           1000

   thyroid and renal function, haematinics, autoantibodies) was normal.
   Patient 4 had been on IDV 800 mg tds for 4 years but was changed to a
   boosted regime (IDV 800 mg bd plus RTV 100 mg bd) to improve adherence.
   5 months later he developed dry skin and lips.

                                                                                                                                                                    APV            IDV         LPV          NFV         RTV        SQV hg SQV sg
   Patient 5                                                                                                                                                       500-700 mg   400-800 mg   400/533 mg   1250 mg     400-600 mg      400-1800 mg
                                                                                                                  Figure 1
   Had been on amprenavir (APV) 750 mg bd for 4 months when he began
   complaining of lethargy, nausea and anorexia.

   Patient 6                                                                                                      1.   Dieleman et al AIDS 2002 16 737-745
                                                                                                                  2.   Burger et al Abstract 6.2a 2nd International workshop on Clinical Pharmacology of HIV Therapy
   Complained of severe nausea shortly after commencing a regimen of                                              3.   Marzolini et al AIDS 2001 15 71-75
   lopinavir (LPV) 400 mg bd plus RTV 100 mg bd (Kaletra 3 capsules bd).                                          4.   Gatti et al AIDS 1999 13 2083-2089

                                                Presented at the 6th International Congress on Drug Therapy in HIV Infection, Glasgow, November 2002, abstract P173

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