1 The Sixth International Congress on Drug Therapy in HIV Infection took place in Glasgow, UK, on November 17-21, 2002. Pharmacological aspects of antiretroviral therapy were covered in both oral and poster presentations. Here we highlight the key issues addressed in the following areas: Therapeutic Drug Monitoring. Intracellular Drug Measurements and Drug Efflux Transporters Reverse Transcriptase Inhibitors (Nucloside, Nucleotide, Non-nucleoside) Protease Inhibitors (PI) Protein Binding Pharmacokinetic Models THERAPEUTIC DRUG MONITORING (TDM) David Burger [1] from The Netherlands opened the pharmacology session with a plenary talk entitled: Therapeutic drug monitoring: does it make a difference?. Therapeutic drug monitoring (TDM) has been included as part of the diagnostic set up for HIV infected patients on antiretroviral therapy in the national guidelines of different countries such as France, UK and The Netherlands. TDM has been shown to be particularly useful in patients with coinfections, drug related toxicity, drug-drug interactions, severe hepatic failure, paediatric patients and, in some situations, to monitor patient adherence. To improve the applicability of TDM, Dr Burger presented the 10 Commandments that will be published on www.hivpharmacology.com. Forsyth et al. [2] showed how TDM can be used to reduce the risk of HIV treatment intolerance and discontinuation. Sixteen out of 78 TDM requests in their clinic in 2001 were for suspected drug toxicity. Six patients had high drug levels and dose adjustments led to improvement of symptoms; examples are shown in Table 2. Table 2 Patient Drug (mg) Symptoms C trough -fold increase compared to MEC WT Dose Adjustment 1 NFV 1250 BID diarrhoea 8.5 1000 BID 2 NFV 1250 BID diarrhoea 3.3 1000 BID 3 IDV/RTV 800/100 BID dry skin, pruritus 11 600/100 BID 4 IDV/RTV 800/100 BID dry skin, pruritus 8.8 600/100 BID 5 APV 750 BID nausea 8.3 600 BID Gibbons et al. [3] presented a retrospective analysis on efavirenz (EFV) and nevirapine (NVP) trough concentrations in patients with hepatic dysfunction (according to liver function tests and/or positivity for HCV status) from the Liverpool TDM Service dataset. Out of >1000 requests for NNRTI assays, 19 patients were identified as fulfilling the criteria (15 on EFV and 4 on NVP). Patients on EFV who were HCV+, but with normal transaminases had plasma concentrations within the therapeutic range, while 5/9 patients with abnormal transaminases had high plasma concentrations. All 4 patients on NVP had high plasma drug concentrations. These data suggest HCV status does not predispose to high NNRTI concentrations, while HIV/HCV co-infected patients with evidence of transaminitis are more likely to have high NNRTI plasma concentrations. Therefore, TDM may have a role in reducing the risk of drug toxicity in such patients.
2 Antinori et al. and Trotta et al. [4,5] from the AdICONA Study Group presented data on the use of TDM to monitor patient adherence to the ARV regimen. The authors observed a correlation between subjective measures of non-adherence (patient-reported and physicianestimated) and plasma drug levels or viral load: self-reported adherent patients were more likely to have adequate plasma drug concentrations than non-adherent patients. These measurements were associated with the risk of subsequent viral rebound, suggesting the usefulness of a questionnaire on adherence when viral load is suppressed, in order to identify those patients at higher risk of virological failure. Boffito et al. [6] presented five case reports where the information given by TDM improved consistently the management of difficult patients on ARVs (Table 3). Table 3 Condition PK parameter Result Conclusion Fungal infection Tuberculosis Gastrectomy (no gastric acidity) Moskovitz-like syndrome LPV C trough at steady state (mean of 3 determinations) when co-administered with ketoconazole LPV C trough at steady state (mean of 3 determinations) when administered without ketoconazole 12931 ng.ml -1 7703 ng.ml -1 LPV AUC at steady state when 163,995 ng.h.ml-1 administered without rifampicin LPV AUC at steady state when 5,805 ng.h.ml-1 co-administered with rifampicin LPV C trough first week of LPV/r (mean of 8 determinations) 4,411ng.mL -1 LPV C trough at steady state 4,864 ng.ml -1 C trough at steady state 30,000 ng.ml -1 LPV C trough at steady state 12439 ng.ml -1 Pleural effusion (Kaposi s sarcoma) Pleural fluid LPV concentration 12691ng.mL -1 12h drug intake Ketoconazole increased LPV concentration by 50%. Boosting effect over RTV enhancement. LPV AUC was decreased by 90% during co-administration with an antituberculosis rifampicin containing regimen The absence of gastric acidity did not influence LPV absorption. LPV values are comparable to effective LPV plasma concentrations [Murphy et al. AIDS 2001] LPV C trough was very high if compared to LPV plasma concentrations previously published [Murphy et al. AIDS 2001] plasma LPV = pleural fluid LPV Boffito et al. [7] observed a modest intra-individual variability (coefficient of variation: 34%) in LPV C trough in HIV+ subjects (n=18, 5-8 plasma drug measurements for each subject) attending an out-patient clinic where dose intake was not witnessed.
3 Noack et al. [8] investigated the usefulness of TDM in 30 HIV+ patients during treatment failure. 57% of the patients were on 2 NRTIs + PI, 40% on 2 NRTIs+NNRTI, 3% on 2NRTIs+NNRTI+PI. Forty-three % of the patients had insufficient drug concentrations, 77% showed NRTI mutations, 50% NNRTI and 83% PI mutations. The reasons for failure are illustrated in Table 4. Table 4 % of Patients Reason for Failure 40 Resistance alone 30 Insufficient drug levels + resistance 13 Drug levels < published MECs 17 Both TDM results and resistance testing could not explain therapy failure Oette et al. [9] investigated the PKs of EFV when co-administered with rosiglitazone, a drug which is currently under investigation in vivo for the treatment of lipodystrophy, in 7 HIV+ patients. Co-administration of rosiglitazone (4 mg) seemed to reduce EFV bioavailability. Moreover, mean serum level of EFV was decreased by 12%, AUC by 8%, Cmax by 43% and Cmin by 41%, suggesting the need of performing TDM of EFV routinely during this coadministration. Paar et al. [10] compared NFV trough concentrations in patients who had been on successful NFV regimens for at least one year (n=32) with NFV C trough reported in PK studies completed during drug development. They observed a wide variability in trough values and a significant difference between morning and evening values in 9 patients, suggesting that TDM, particularly using C trough as a marker, may not be an appropriate measurement for predicting the success of a NFV-containing regimen. Leen et al. [11] measured T-20 (90 mg SC) plasma concentrations in a 26 year old HIV+ male patient with renal impairment (creatinine clearance 244 µmol/l) (Table 5). Plasma T-20 levels were similar to data with normal renal function. Table 5 Sample Time (h) Mean T-20 (µg/ml) 1 0 0 2 1.25 0.48 3 3.42 2.73 4 6.92 5.20 5 11.42 3.62 Vogel et al. [12] measured cyclosporin A plasma concentrations in a 43 year old HIV+ patient who underwent a liver transplant and was treated with LPV/RTV (400/100 mg BID). Concomitant administration of LPV/RTV led to considerable boosting of cyclosporin A levels, showing that only 1/20 of cyclosporin A was needed to achieve adequate drug levels in plasma. Therefore TDM is needed in HIV+ patients with organ transplantation and ARVs.
4 Lyall et al. [13] measured LPV/RTV plasma concentrations in 20 children routinely (number of determinations = 53) and observed that 21% and 26% of the levels where low or high, respectively (based on the normal range of concentrations in adults. Seven of the eight children resulted to be non-adherent to the ARV regimen. The same authors [14] also measured EFV plasma concentrations in 12 children (number of determinations = 29) and confirmed the usefulness of TDM in the assessment of adherence to ARV regimens in children. INTRACELLULAR DRUG MEASUREMENTS AND DRUG EFFLUX TRANSPORTERS Patrick Hoggard, from the University of Liverpool, discussed the impact that the expression of efflux transporters P-glycoprotein (P-gp) and MRP1 have on the intracellular accumulation of lopinavir (LPV) and ritonavir (RTV) in HIV infected patients receiving Kaletra and the effect that protease inhibitor (PI) containing regimens may have on multidrug resistance transporter expression [15,16]. Dr Hoggard showed a median (range) intracellular/plasma AUC 0-12 ratio of LPV and RTV of 1.56 (0.67-3.80) and 5.28 (2.45-9.61), respectively and a significant correlation between the accumulation of LPV and RTV (r 2 =0.562, p=0.008). Moreover, a statistically significant relationship was observed between the expression of P-gp and the intracellular accumulation of LPV (p=0.028, Pearson s correlation). The median intracellular accumulation of RTV was significantly higher in patients receiving LPV/RTV compared to previous studies with patients receiving RTV only (p<0.001). In relation to the effect of PIs on efflux transporters in PBMCs obtained from HIV+ patients, no sole PI regimen seemed to alter P-gp or MRP1 expression. Therefore, factors other than PI induction seem to be important in the inter-individual variability in transporter expression in PBMCs. Azoulay et al. [17] presented an immunoassay method for the quantification of LPV, RTV, EFV, and NVP in plasma and peripheral blood monocytes of HIV patients. The method was cross-validated by HPLC measurements. The authors observed a wide inter-patient variability in intra- to extra-cellular drug concentration ratios (i.e. RTV ranging between 0.8 and 19.5). REVERSE TRANSCRIPTASE INHIBITORS (N-, Nt-, NN-, RTI) Jacques Grassi [18] showed how the intracellular metabolism of AZT leads to the production of significant levels of d4t triphosphate in HIV-infected patients. The phosphorylated forms of nucleoside-reverse transcriptase inhibitors (NRTIs) have been measured by a newly developed direct LC/MS/MS technique. Intracellular d4t-tp concentrations measured in AZT-treated patients were shown to represent between 3 and 37% of the corresponding AZT- TP concentrations and to be in the lower range of d4t-tp concentrations measured in d4ttreated patients, indicating that d4t-tp could participate in the antiretroviral activity and/or toxicity of AZT. Moreover, this observation brings a new light on the cross-resistance observed between AZT and d4t. A pharmacokinetic evaluation of lamivudine (150 mg), stavudine (40 mg) and nevirapine (200 mg) given as fixed dose combination pill was presented by Dr Gogtay [19] from Cipla Ltd, Mumbai, India. The co-formulation was shown to be bioequivalent to the reference compounds given separately.
5 Taylor et al. [20] measured abacavir (ABC) and 3TC concentrations and antiviral activity, after commencing therapy, in the blood plasma (BP) and seminal plasma (SP) of 10 HIV+ men. ABC concentration in semen reached similar values to those achieved in BP. The disposition dynamics of ABC have been observed to be different in blood and semen with a lag in maximum semen concentrations that are in general higher than maximum blood concentrations. Moreover, the absolute seminal concentrations of 3TC are at least 2-fold higher than BP irrespective of the time of sampling. The PKs of 3TC in SP are markedly different than the PKs in BP. For example, 3TC not only appears to accumulate within the genital tract but also persists at high concentrations for the entire dosing interval in contrast to the rapid decline seen in BP. A potent antiviral effect was observed in BP and SP in 7/8 patients receiving 24 weeks of 3TC and ABC-containing regimens. Schlemmer et al. and Benech et al. [21,22] described LC/MS/MS methods for the quantification of NRTIs in plasma and intracellularly. Active (triphosphate, TP) NRTIs and the ratio with their endogenous competitors can now be quantified on the basis of the same LC/MS/MS and from the same blood sample. Inter-patient variability was 50% for d4t-tp and dda-tp, d4t half-life was 7 h and a positive correlation between AZT-TP and 3TC-TP as well as between dda-tp and d4t-tp was observed. Kearney et al. [23] investigated the PK drug-drug/drug-food interactions of ddi-ec and TDF in healthy volunteers and observed: I) ddi had no effect on TDF PKs; II) ddi systemic exposure was increased by 48% when dosed in a fasted state, 2 h before TDF with a light meal; III) ddi exposure was similarly elevated when given with TDF and a light meal. The same authors [24] also investigated the PKs of TDF (300 mg) in subjects with normal and varying degrees of renal impairment, including those with end stage renal diseases undergoing haemodialysis and observed that TDF PKs are not affected to an extent requiring dose modification in subjects with a creatinine clearance 50 ml/min. However, a dose modification is necessary in subjects with a clearance < 50 ml/min. TDF was efficiently removed from the circulation (extraction ratio ~ 50%) during a standard, 4h haemodialysis session. Rodman et al. [25] evaluated the potential for an intracellular interaction between tenofovir (TDF) and ddi in vitro in human PBMCs and observed that there are no apparent changes in the extent of the formation of the active metabolites of either ddi or TDF with concurrent incubation at extracellular concentrations similar to those that would be found in patients receiving combination therapy at currently recommended doses, suggesting that the increased systemic exposure of ddi, when given with TDF, should not be further complicated by an intracellular interaction.
PROTEASE INHIBITORS (PI) Report on HIV6, Glasgow, November 2002 6 Gatti et al. [26] studied 45 HIV+ patients on different dosage of APV containing regimens to evaluate predictors of amprenavir (APV) trough (C trough ) and peak (C peak ) concentrations in deep salvage therapy setting and showed: a) a median (range) C trough and C peak of 1.36 (0.12-4.89) and 5.29 (1.05-22.7) µg/ml, respectively; b) at multivariate analysis the variables with a significant effect on C trough were APV dose, gender and efavirenz (EFV) intake; c) differences in female and male patients C trough (1.11 vs 1.45 µg/ml); d) a lower APV C trough in patients on EFV vs patients not taking EFV (0.90 vs 1.42 µg/ml); e) a lower APV Cpeak in patients on LPV7RTV compared to patients not taking LPV/RTV (2.85 vs 5.40 µg/ml). Maserati et al. [27] studied nelfinavir (NFV, 1250 mg BID or 750 mg TID) pharmacokinetics (PKs) in a cohort of HIV+/HCV+ (n=21; group IA: normal to grade 1, group IB grade 2, according to ALT levels) co-infected patients with different degrees of liver impairment and compared the different parameters to HIV+/HCV- controls (group II; n=42) and showed that oral clearance of NFV and M8/NFV ratio were significantly reduced in co-infected patients (Table 6). This seemed to be related to the degree of liver function impairment as measured by ALT levels. Table 6 Group Median (range) NFV oral clearance (L/h/Kg) Median (range) NFV AUC 0-24 (µg.h/ml) AUC 0-24 NFV/AUC 0-24 M8 IA 0.35 (0.24-0.97) 113.2 (53.88-177.0) 0.15 IB 0.25 (0.09-0.50) 165.9 (91.10-442.35) 0.10 II 0.51 (0.1-2.1) 69.93 (6.67-275.94) 0.33 Mauss et al. [28] evaluated the boosting effect of RTV 200 mg BID on LPV and APV when co-administered and showed that APV levels were decreased substantially (p<0.001) following the addition of LPV and LPV levels were reduced about 50% (AUC 0-12 56.1 vs 100 µg.h/ml) compared to historical study data [Murphy et al. 2002]. There was no significant increase in median AUC 0-12 of LPV and APV in patients treated with RTV 200 mg BID compared to patients on RTV 100 mg BID [Mauss et al. 2002]. However, the authors stated that therapeutic drug levels could be reached in patients with the combination of APV and LPV boosted by RTV. Lafeuillade et al. [29] studied HIV-RNA dynamics, resistance and LPV diffusion in semen in 22 HIV+ men and observed median LPV levels in SP of 185 ng/ml (range: 0-7161) and a median LPV SP/BP ratio of 0.056, showing a high inter-individual variability. However, HIV-RNA was undetectable in the semen of most patients. Harris et al. [30] investigated the efficacy of indinavir (IDV) 600 mg BID plus LPV/RTV. IDV had no effect on the PKs of LPV. Moreover, the co-administration of IDV and LPV/RTV was well tolerated and had a substantial antiviral effect in both patients with wild type (WT) HIV and in patients with high levels of resistance to PIs.
7 Stephan et al. [31] assessed the PKs of LPV, SQV and RTV in 2 groups of HIV+ patients: group 1 (n=43) on LPV/RTV 400/100 and SQV-soft gel 1000 BID, without NRTIs; group 2 (n=32) on SQV-soft gel 1000 mg and RTV 100 mg plus 2-3 NRTIs. The authors observed a wide inter-patient variability in SQV AUCs, but the addition of LPV to a RTV-boosted SQV regimen did not have any effect on SQV plasma exposure, suggesting there is no need for PI dose adjustment in SQV/LPV/RTV regimens. Interestingly, RTV trough levels were found to be significantly lower in group 1, compared to group 2, without resulting in decreased plasma exposure of SQV. Wasmuth et al. [32] assessed the PKs and tolerability of IDV (600 vs 400 mg BID) boosted by RTV (100 mg BID) in 16 healthy volunteers. IDV C max, C min and AUC were significantly lower during intake of IDV/RTV 400/100 (p<0.001), with 3/15 subjects revealing C min values below the recommended threshold of 0.10 mg/l. However, tolerability was lower in the 600/100 group. PROTEIN BINDING Almond et al. [33] presented data on nevirapine (NVP) plasma protein binding in 52 HIV+ patients, showing a NVP unbound percentage ranging between 22.1 and 42.5%. Inter-patient variability in total and unbound concentrations and unbound percentages expressed as coefficient of variation (cv) were 42%, 43% and 17%, respectively. Boffito et al. [34] for the Forum for Collaborative HIV Research, Washington DC, USA, presented some of the key issues regarding protein binding of ARV drugs highlighted during a Consensus Meeting which took place in June 2002. The panel concluded that the impact of plasma protein binding on the pharmacokinetics of highly bound drugs is well characterised and this knowledge should generally be applicable to ARV drugs. However, clinical studies are needed to investigate unbound fractions and concentrations and the impact that changes in plasma proteins responsible for drug binding can have on drug efficacy. Standardisation of the analytical methods for the measurement of unbound drug is urgently required. With this in mind, the panel formulated a list of questions, which need to be addressed to help understand the role of protein binding in the clinical pharmacokinetics of ARVs: a) What is the inter-individual variability in protein binding for each ARV drug? b) Could HIV infection itself and/or concomitant disease influence plasma protein concentrations and thereby alter pharmacokinetic parameters such as half-life, volume of distribution and clearance? c) Do unbound drug concentrations correlate with clinical outcome better than total concentrations? d) Would measurement of the unbound concentration in plasma of patients give more meaningful information than total drug concentration and should this be considered in routine therapeutic drug monitoring of ARV agents? e) What is/are the best method(s) for measuring the unbound concentration of drug both in vitro (for IC 50 determination) and in vivo? In addition the panel concluded that clinically relevant drug interactions do not occur at the level of protein binding.
PK MODELS Report on HIV6, Glasgow, November 2002 8 Hsu et al. [35] illustrated a mathematical HIV treatment model to assess how various adherence rates affect the probability of resistance development for ARV drugs with different PKs and resistance properties. EFV (very high IQ values relative to HIV WT, but significantly reduced IQ relative to mutants because of large resistance step sizes), NFV (low IQ values relative to both HIV WT and mutants and small initial resistance step sizes) and LPV/RTV (high IQ values relative to HIV WT and to initial mutants, small resistance step sizes; terminal half-life is 9-10h and 1-2 h during missed doses [Kempf et al. 2002]). The simulation demonstrated that: a) adherence rate have distinctively different effects for the three model drugs in treatmentnaïve patients; b) PK, resistance step size and adherence rate are contributing factors to resistance development during drug therapy; c) the relationship between adherence rates and probability of drug resistance development are related to drug-specific PK properties and resistance step sizes; d) during good adherence, the probability of drug resistance development can be reasonably predicted on drug-specific PK profiles and resistance step sizes; e) the probability of resistance development is lower if drug concentrations are high enough to also suppress initial mutants; f) long elimination half-life drugs may increase the probability of developing drug resistance during inconsistent adherence, while if drug concentrations decline rapidly, during missed doses, this probability is low due to the short residence time inside selective concentration windows. Kurowski et al. [36] performed a population based analysis of APV C trough assessed during the course of routine TDM. A model to describe plasma C trough and to allow the prediction in patients treated with defined dosage regimens was developed and applied to 89 samples obtained from patients on APV 600 mg BID boosted by either 100 or 200 mg BID RTV. The analysis of normal probability plots shows 2 distinct populations of patients with APV C trough > and < 500 ng/ml. C trough < 500 may be due to non-compliance or pharmacogenetic differences and requires further investigation.
REFERENCES Report on HIV6, Glasgow, November 2002 9 1. Burger D. Therapeutic drug monitoring: does it make a difference? Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [PL 8.1]. 2. Forsyth et al. The use of therapeutic drug monitoring (TDM) in the management of HAART related toxicity. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P173]. 3. Gibbons et al. Therapeutic drug monitoring of NNRTIs in patients with hepatic dysfunction. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P174]. 4. Antinori et al. Predictive value of self-reported non-adherence (non-adh) and drug plasma levels on viral rebound in HAART-treated patients with undetectable viremia. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P177]. 5. Trotta et al. Patient-report, physician estimate and drug plasma levels as measures for adherence to HAART in the AdICONA study. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P89]. 6. Boffito et al. Five case reports advocating the use of therapeutic drug monitoring of lopinavir/ritonavir. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P184]. 7. Boffito et al. Intra-individual variability in lopinavir plasma trough concentrations support therapeutic drug monitoring. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P185]. 8. Noack et al. Significance of therapeutic drug monitoring for HIV positive patients with treatment failure receiving high antiretroviral therapy (HAART). Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P188]. 9. Oette et al. Rosiglitazon in the treatment of combined HIV-associated lipodystrophy syndrome: impact on the bioavailability of efavirenz and safety of medication. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P189]. 10. Paar et al. Serum nelfinavir (NFV) levels after 1 year of NFV-based HAART. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P190]. 11. Leen et al. PK of T-20 in a patient with impaired renal function. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P191]. 12. Vogel et al. Management of drug to drug interactions between cyclosporin A and the proteinase inhibitor lopinavir/ritonavir in an organ-transplanted HIV-infected patient. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P192]. 13. Lyall et al. Lopinavir concentrations in children. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P76]. 14. Lyall et al. Efavirenz (EFV) concentrations in children. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P77]. 15. Hoggard et al. The intracellular accumulation of (LPV) and ritonavir (RTV) is influenced by the expression of efflux transporters P-glycoprotein and MRP1 in HIV-infected patients receiving Kaletra. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [PL8.2]. 16. Ford et al. The effect of protease inhibitor containing regimens on multidrug resistance transporter expression. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [PL8.2]. 17. Azoulay et al. Immunoassay, a simple and efficient method for plasmatic and intracellular quantification of antiviral drugs. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P193]. 18. Grassi et al. Intracellular metabolism of AZT leads to the production of significant levels of d4t triphosphate in HIV-infected patients. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [PL8.3].
10 19. Gogtay et al. A pharmacokinetic evaluation of lamivudine, stavudine and nevirapine given as fixed dose combination pill versus the same three drugs given separately in healthy human volunteers. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [PL8.4]. 20. Taylor et al. Abacavir and lamivudine reach high concentrations in the semen of HIV-1-infected men. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P168]. 21. Schlemmer et al. LC/MS/MS assay for plasma and intracellular nucleoside reverse transcriptase inhibitors. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P171]. 22. Benech et al. Direct LC/MS/MS assay for intracellular AZT, d4t, ddi and 3TC tri-phosphates and their competitors dttp, datp, dctp and dgtp. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P172]. 23. Kearney et al. Tenofovir DF (TDF) and didanosine EC (ddi EC): investigation of pharmacokinetic (PK) drug-drug and drug-food interactions. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P186]. 24. Kearney et al. Pharmacokinetics following single dose administration of tenofovir DF in patients with renal impairment. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P4]. 25. Rodman et al. Intracellular metabolism of didanosine (ddi) and tenofovir (TFV) in human peripheral blood mononuclear cells (PBMCs). Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P180]. 26. Gatti et al. Predictors of amprenavir parameters of drug exposure in heavily pre-treated HIV-positive patients. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P165]. 27. Maserati et al. HCV coinfection with normal or low grade ALT modifies nelfinavir disposition in HIVpositive patients. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P166]. 28. Mauss et al. Does ritonavir 200 mg bid inhibit the interference of lopinavir with amprenavir plasma concentration in HIV-positive patients? Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P167]. 29. Lafeuillade et al. HIV-1 RNA levels, resistance, and drug diffusion in semen compared to blood in patients receiving a lopinavir (LPV)-containing regimen. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P169]. 30. Harris et al. Rescue therapy with indinavir (IDV) 600 mg twice daily and lopinavir ritonavir (LPV/RTV): baseline resistance, virologic response and pharmacokinetics (PKs). Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P170]. 31. Stephan et al. Saquinavir plasma exposure is not decreased in lopinavir/ritonavir co-administration compared to standard ritonavir booster by AUC in steady-state condition. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P176]. 32. Wasmuth et al. Combination of reduced dose indinavir and ritonavir in healthy volunteers. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P182]. 33. Almond et al. Nevirapine protein binding in HIV infected individuals. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P164]. 34. Boffito et al. Protein binding of antiretroviral drugs. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P183]. 35. Hsu et al. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of HIV therapy. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P179]. 36. Kurowski et al. A population based analysis of amprenavir trough concentrations assessed in the course of therapeutic drug monitoring. Sixth International Congress on Drug Therapy in HIV Infection, 17-21 November 2002, Glasgow, UK. [P187].