icon-folder.gif   Conference Reports for NATAP  
  3rd Pharmacology Workshop
April 11-13, 2002, Washington, DC,
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Report From the 3rd Pharmacology Workshop
Reported by Jennifer King for NATAP, PharmD, University of Alabama at Birmingham
  Table of Contents:
  • switching from 400/400 RTV/SQV to 1000/100 SQV/RTV

  • Kaletra plus 1000 mg saquinavir without nukes

  • Drug levels of amprenavir with low dose ritonavir taken once daily after adding efavirenz

  • Drug levels of saquinavir using cimetidine as an alternative booster to ritonavir

  • Protein binding and its effect on HIV therapy efficacy

  • Gender and Drug Levels in Blood and Genital Tract

  • TMC-125 Drug Levels

  • Preliminary research for AZT once daily dosing

  • Comparison of drug levels between buffered and enteric-coated didanosine in HIV-infected children

  • Drug levels in HCV coinfected patients

  • Kaletra and amprenavir interactions in healthy volunteers

  • Amprenavir and saquinavir interactions in drug experienced patients

  • Kaletra plus saquinavir and nukes in heavily pre-treated patients

  • Delavirdine plus Kaletra interactions

  • Invirase vs Fortovase Blood Levels, once or twice daily

Below is a summary of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy that took place on April 12-13 in Washington D.C. This summary will briefly review abstracts presented at the meeting. Not all abstracts will be covered, but the posters should be available online at www.virology-education.com. At the end, we conclude with some observations related to discussions during the meeting on the importance of protein binding and the direction of therapeutic drug monitoring for antiretrovirals.
Edit. Note: this conference is a scientific one and the information and reporting of it is cumbersome due to the scientific language and concepts used which are asociated with drug blood levels (pharmacokinetics). As well, these studies are generally preliminary small scientific studies meant to explore ideas which are not yet ready for clinical application and use by doctors and patients. However, there are a few clinically interesting findings that appear to have interest related to current clinical practice. First, studies reported that the old harg-gel formulation of saquinavir called Invirase and the same drug levels as Fortovase when boosted with low-level ritonavir. As a result, patients and doctors may want to consider using Invirase in PI-boosting situations rather than Fortovase. You can read the studies below. Another study with interesting implications in current practice was presented by Schlomo Staszewski and a German research group exploring the use of 1000 mg saquinavir plus Kaletra in an NRTI-sparing regimen for patients who may have exhausted nuke options. These studies are reviewed below.
The Workshop began with an invited lecture from Dr. Mark Kline on drug development challenges in pediatrics including those in developing countries. Dr. Kline spoke on the difficulties that arise with antiretroviral use in children and physiological differences between pediatric and adult patients that influence pharmacokinetics. He also discussed programs that have been developed in Romania to address international pediatric HIV issues and integration of clinical services and research for these populations. Edit note: half of all peds cases in Europe are in Romania. Dr. Kline and his colleagues have made significant progress toward the challenges of pediatric HIV care in the developing world. Day 2 started off with an excellent overview of pharmacogenetics by Dr. David Haas from Vanderbilt University. He presented an overview of the history and current status of pharmacogenetics, discussed laboratory approaches for analyses and strategies for study designs, and suggested attractive areas for future pharmacogenetic research. Both lectures were well received and probably set a new precedence for future meetings. Edit. Note: Pharmacogenetics is the study of a patient's genetic makeup in order to see if their genes affect their response to antiretroviral therapy or the side effects and toxicities of the drugs. For example, recent research has suggested that patient's with a certain gene may be more likely to experience hypersensitivity to abacavir. If this is found to be true in ongoing research perhaps their could be a genetic patient test to screen for this.
One important theme from the meeting included new concepts in pharmacokinetic enhancement of protease inhibitors. An increased use of dual protease inhibitor regimens as part of salvage therapy has led to innovative ways to increase efficacy while decreasing side effects and pill burden. Several studies evaluated the pharmacokinetics and tolerability of these regimens.
Bill O'Brien and colleagues evaluated the PK of HIV-infected patients switching from SQV-sgc 400mg/RTV 400mg BID to SQV-sgc 1000mg/RTV 100mg BID.
Switch of Saquinavir 400 mg/Ritonavir 400 mg to Saquinavir 1000 mg/Ritonavir 100 mg during BID four drug antiretroviral therapy in patients with viral load less than 200 copies/ml.
Abstract 2.1: W.A. O'Brien, D. Rojo, E. Acosta, F. Felizarta, D. Pearce, D.T. Jayaweera, F. Visnegarwala.]
Study patients were on the 400/400 regimen for at least 3 months prior to enrollment and were also receiving 2 or more NRTIs. Inclusion criteria consisted of a plasma HIV RNA of <400 copies/ml within 2 weeks of the baseline visit. Twenty-one patients were included in the study with 11 patients switching to 1000/100 BID and 10 patients continuing with the 400/400 BID regimen. Two patients in the 1000/100 group discontinued the regimen due to pancreatitis and one patient from the 400/400 group discontinued the regimen with sudden death. At week 24, 0 patients in the 1000/100 group had a plasma HIV RNA > 400 copies/ml compared with 2 in the 400/400 group. Patients in the 1000/100 group showed a trend towards reduction in fasting triglyceride (488 to 329 mg/dl) and cholesterol (259 to 227 mg/dl) levels from baseline to 6 months. In the patients remaining on 400/400 tryglcerides and cholesterol increased slightly. O'Brien reported tolerability was improved with patients in the 1000/100 group and was likely related to the reduction in RTV drug concentrations seen in this group compared with drug levels seen in the 400/400 group.
Efficacy of RTV-enhanced double PI therapy without a NRTI was evaluated in 27 antiretroviral-experienced patients with multi-NRTI resistance or NRTI toxicity. Edit. Note: This early study presents an interesting concept in treatment, PI therapy without nukes, and an interesting new combination saquinavir plus Kaletra.
Kaletra + 1000 mg Saquinavir Without NRTIs
Pharmacokinetic profile monitoring as an augmentation to therapy evaluation in patients taking a simple boosted double protease inhibitor regimen of Lopinavir/R plus Saquinavir without reverse transcriptase inhibitors

Abstract 2.4: S. Staszewski, B. Dauer, C. Stephan, P. Gute, S. Klauke, M. Sturmer.
Patients received SQV-sgc 1000mg BID in addition to LPV 400mg/RTV 100mg. Individual 24-hour PK drug levels were assessed in all 27 patients. SQV Cmin was 1250 ng/mL, which was within the expected range (authors state the suggested SQV Cmin is 216 ng/mL). LPV levels were not negatively affected by SQV co-administration. Staszewski reported that between 12 and 24 hours post-dose, the LPV level fell below the estimated IC50, suggesting that this regimen is not suited for once daily dosing. At week 17, 55% of patients had a plasma HIV RNA <50 copies/mL.
Edit. Note: This is a small (n=27) pilot study in treatment-experienced patients. The authors are studying this nuke-sparing regimen because they have found patients in the Frankfurt Cohort Study often have lost their NRTI treatment options due to resistance or toxicity but may have PI options. They reported preliminary results after following patients for 17 weeks. The researchers reported cholesterol increased but triglycerides did not. CD4 count increased by 70 and viral load declined by 3.4 log. This study is continuing and further results are expected to be reported in the future. 81% had <400 copies/ml after 15 weeks, and 78% had >2 log viral load reduction after 14 weeks. Authors reported that the viral failures tended to have lower saquinavir levels, more previous PI use, more previous therapy duration, more prior ART use, and lower CD4 counts (51 vs 214).
Pharmacokinetics of APV and low dose RTV with and without EFV were assessed in HIV-infected patients.
An assessment of plasma Amprenavir (APV) pharmacokinetics (PK) following administration of Agenrease (APV) and low dose Ritonavir (RTV) QD in combination with Efavirenz (EFV) in HIV-infected adult subjects (COL30500).
Abstract 2.2: R. Wood, M.B. Wire, T. Lancaster, Y. Lou, C. Orrell, T. Scott. ŠŠ.
An assessment of plasma Amprenavir (APV) Pharmacokinetics (PK) following long-term administration of Agenerase and low dose Ritonavir (RTV) QD in HIV-infected adult subjects (APV20001 and COL30500).
Abstract 2.6: R. Wood, M.B. Wire, T. Lancaster, Y. Lou, K. Levesque, O. Naderer, T. Scott.]
Patients in arm A received APV 1200mg QD, RTV 200mg QD, 3TC 150mg BID and ABC 300mg BID for 48 weeks. Eight subjects underwent plasma APV PK sampling on week 2 and 48. AUCt,ss, Cmax,ss and Ct,ss for APV were maintained between week 2 and 48 for all 48 patients. Plasma HIV RNA was <50 copies/mL in all 8 subjects by end of the study. Thirteen subjects were then selected for arm B to receive EFV 600 mg QD in addition to the above regimen. Additionally, the RTV dose was increased from 200mg to 300 mg QD in these patients. AUCt,ss, Cmax,ss, and Ct,ss for arm A were comparable with arm B. Neurological events (in 54% of 7 patients) were the most common reported adverse events and the authors attributed it to the addition of EFV.
The effect of cimetidine on the PK of SQV-sgc was evaluated in 12 healthy patients.
Pharmacoenhancement of Saquinavir by cimetidine: an alternative booster to Ritonavir.
Abstract 2.8: M. Boffito, L. Trentini, R. Raiteri, S. Bonora, A. Sinicco, H.E. Reynolds, P.G. Hoggard, D.J. Back, G. Di Perri.
SQV-sgc was administered at 1200 mg TID for the first 13 days and at 1200mg BID days 14-26 when co-administered with cimetidine 400 mg BID. Plasma samples were collected at times 0, 1, 2, 4, 8, 12 and 24 hours. Median SQV AUC24 increased from day 13 to day 26 (5.11 and 11.23 mgxh/mL, p=0.041), respectively. Median SQV Ctrough was 107 ng/mL when administered TID and 142 ng/mL when administered BID with cimetidine (p=0.272). A lack of increase in SQV Ctrough may be explained by the short t1/2 of the drug. Overall, cimetidine appeared to have a very modest effect on SQV levels compared with RTV.
Protein binding and its effect on efficacy were discussed at length during the meeting. Opinions varied from protein binding being irrelevant to being very important. Several abstracts were presented on this topic and a brief discussion is included at the end of this review.
One study measured the influence of 1 mg/mL of alpha1-acid glycoprotein (AAG), Human Serum Albumin (45mg/mL) and Human Serum (50%) on PIs.
Influence of binding to human plasma proteins by protease inhibitors may be overestimated in current IQ models
Abstract 3.2: M-P de Bethune, D. Xie, H. Azijn, P. Wigerinck, R. Hoetelmans.
With the exception of IDV, all tested PIs showed a decrease in potency against wild-type HIV-1 in the presence of AAG and HS (50%), but not in the presence of HSA. The decrease ranged from 5- to 75-fold and was proportional to the AAG concentration. The authors concluded that in the presence of 1mg/ml AAG, plasma concentrations of PIs show less than a 5-fold decrease in potency. They concluded that protein binding is not as relevant as previously believed when calculating the inhibitory quotient.
Dale Kempf and colleagues from Abbott Laboratories investigated the serum-free IC50 for LPV and RTV.
Identification of the Serum-Free IC50 for Lopinavir and Ritonavir: A Useful Measure for the Estimation of Inhibitory Quotients in Plasma and Sanctuary Sites
Abstract 3.3: D. Kempf, D. Hickman, S. Vasavanonda, G. Nequist, C. Sanneman, J. Schmidt, R. Bertz, H. Mo, A. Molla, S. Roberts, G.R. Granneman, A. Hsu.
The authors determined that the amount of unbound drug in plasma is concentration-dependent. For example, 6.3% of LPV free fraction is found in 5% fetal calf serum (FCS) while 0.6 % is found in 50% FCS. The serum-free IQ was determined from the following equation: (Ctrough … free fraction) / IC50,free. The serum-free IQ for LPV (without regard to food) was 52. This method may be helpful in assessing the IQ for patients for whom the free fraction of the PI is available. These data suggest protein binding is very relevant when interpreting IC50 values.
Another study evaluated the changes in susceptibility of wild-type virus to PIs and NNRTIs in different concentrations of proteins.
Effects of human serum on protease inhibitor and non-nucleoside reverse transcriptase inhibitor activity in a phenotypic drug susceptibility assay (PhenoSense HIV)
Abstract 3.4: K.L. Limoli, L.H. Trinh, G.M. Heilek-Snyder, J.M. Weidler, N.S. Hellman, C.J. Petropoulos.
Changes in IC50 for IDV, APV, LPV, RTV, SQV and NFV were evaluated in 25%, 50%, and 75% HS. These values were then used to extrapolate the IC50 value at 100% HS. IC50 values for the PIs increased as the %HS increased. Based upon these changes, a protein binding coefficient, (or adjustment factor), termed VPBC (virologic Protein Binding Coefficients), was determined and was similar to previously reported adjustment factors (Molla, et al. Virology 1998;250: 255-62). The VPBC-50% HS compared with the VPBC-100% HS for each PI are as follows: IDV 2.1 and 3.5; APV 3.8 and 10.5; LPV 3.9 and 14.2; RTV 10.2 and 29.7; SQV 14.7 and 28.0; NFV 21.9 and 90.6, respectively. Changes in IC50 for DLV, EFV and NVP were evaluated in 25% and 50% HS. IC50 values for these NNRTIs increased as %HS increased. The effect of different concentrations of AAG on PI fold change was also evaluated. The authors concluded that AAG significantly decreased potency of NFV>APV>LPV>RTV. These results also suggest protein binding is relevant when considering in vitro IC50.
Gender and Drug Levels
There were a few studies discussing the role gender plays in pharmacokinetics and antiretroviral therapy.
Angela Kashuba and colleagues from the University of North Carolina in Chapel Hill evaluated the concentration of PI and NNRTI concentrations in the male and female genital tract.
Comparison of protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) concentrations (conc) in the male (M) and female (F) genital tract (GT)
Abstract 5.3: A.D.M. Kashuba, S. Min, A.H. Corbett, N. Rezk, M.S. Cohen.
Female C12h genital tract/blood plasma ratios were 1.45 for IDV, 0.03 for RTV, 0.05 for LPV, 0.8 for NVP and 0.5 for DLV. The ranking of drug penetration in the female genital tract was IDV>NVP>APV>DEL>LPVĒRTV, which is comparable with the published ranking of drug penetration of IDV>NVP>APV>LPV>RTV in the male genital tract.
Edit. Note: More IDV enters the genital tract of both men and women than enters the blood. For the other drugs studied here more drug enters the blood than the genital tract for both men and women. In other words, it appears from this study that indinavir is better at penetrating the genital tract than the other drugs. Why may this be important? It has been suggested that low antiretroviral drug concentration in the genital tract may promote local development of HIV drug resistance. The authors said this was the first study evaluating whether protease inhibitors and NNRTIs concentrate differently in male and female genital tract fluid. This is a preliminary study and the clinical implications of this study are not clear to me, except that they found no difference between genital tract penetration of drugs between men and women. In this study, multiple cervicovaginal fluid and blood plasma samples were collected from 5 HIV-infected women (35 years of age, range 29-41).
David Burger and colleagues from UMC, Nijmegen, the Netherlands compared LPV plasma levels in HIV-infected females with HIV-infected males.
Lopinavir plasma levels are significantly higher in female than in male HIV-1 infected patients
Abstract 6.5: D.M. Burger, R.J. Muller, M.R. van de Leur, C.J.L. la Porte.
This study reported finding that women had higher lopinavir levels than men and it was related to gender, not weight. In their introduction, the authors reported that it's been recently demonstrated that female HIV-infected patients have a higher risk for toxic indinavir blood levels than male patients (Burger et al. J AIDS 2002; 29: 101). The authors reported they have seen a similar trend in their TDM service for Lopinavir, so they conducted this study.
One hundred and thirty patients (20 females and 110 males) were included. A database of LPV samples was used for PK evaluation. Inclusion criteria for samples consisted of a LPV dose of 400mg q12h and a time window between intake and sampling of 4 to 12 hours. A concentration ratio approach was used for comparison, which may not accurately reflect all patients true drug disposition. Significantly higher LPV levels were observed in female patients than in male patients (11.7 vs. 7.0 mg/L, p=0.02). Body weight showed an inverse relationship with LPV exposure (p=0.007) and female patients had a lower body weight. In a multivariate logistic regression model, gender and not body weight was significantly related to increased LPV exposure.
M.B. Regazzi and colleagues from Italy evaluated the potential gender differences in NVP disposition.
Analysis of potential gender difference in Nevirapine disposition in HIV-infected patients
Abstract 4.4: M.B. Regazzi, P. Villani, E. Seminari, F. Marubbi, G Meneghetti, M. Cusato, R. Maserati.
Eleven men and 11 women received NVP 400 mg QD plus 2 NRTIs for at least 4 weeks. Plasma samples were collected over 24 hours for PK evaluation. Mean Cmax and AUC24 values were 44% (p=0.042) and 20% (p=ns) higher in females than in males, respectively. Weight was statistically different between males and females (70.4 vs.54.3 kg, p<0.005).
Edit. Note: the authors were unable to conclude whether differences in NVP blood levels were due to weight, gender, or body composition. They suggested the higher blood levels might account for the higher incidence of NVP-induced rash in women than men.
Several studies evaluated the pharmacokinetics of new antiretroviral agents, new formulations of available antiretrovirals and existing antiretrovirals.
The pharmacokinetics of TMC125, an investigational NNRTI, were evaluated in HIV-infected patients and healthy volunteers.
Pharmacokinetics of TMC125 in HIV-infected patients and healthy volunteers
Abstract 6.1: S. Piscitelli, P. Baede, K. DeDier, G. Van't Klooster, N. Graham.
TMC125 was administered in doses from 100mg to 900 mg BID to HIV-infected patients for a maximum of 8 days. Over 250 healthy volunteers received single and multiple doses of 50mg to 1600mg BID for up to 21 days. A single oral dose produced a Tmax of 2-4 hours and a t1/2 of 30-40 h. Administration with food increased the oral bioavailability of TMC125 approximately 3-fold compared with fasting conditions. Doses of 900mg BID in HIV-infected patients produced a Cmax and Cmin of approximately 390 ng/mL and 200 ng/mL, respectively. TMC125 is >99% protein bound and the addition of HS does not shift the susceptibility curve. TMC125 Cmin in HIV-infected patients were lower compared with those in healthy volunteers.
Pete Anderson and colleagues from the University of Colorado characterized the intracellular triphosphate concentrations in antiretroviral naīve adults.
The pharmacokinetics of zidovudine-triphosphate (ZDV-TP) in HIV-infected adults
Abstract 6.3: P.L. Anderson, R. Brundage, D. Weller, S. Kawle, L. Bushman, C.V. Fletcher.
The 2-hour zidovudine-triphosphate (ZDV-TP) concentration at week 2 and baseline CD4 count were correlated (p=0.03) but not the weeks 28 or 56 ZDV-TP and corresponding CD4 counts. In patients with <100 CD4 cells at week 2, ZDV-TP production was increased 4-fold (p<0.01). The modeled ZDV-TP half-life was approximately 7 to 10 hours, which is longer than a previously estimated value of 3 hours. The authors concluded that these data provide a rationale to investigate once daily ZDV dosing.
The pharmacokinetics of buffered and enteric-coated didanosine were evaluated in HIV-infected children.
Pharmacokinetic comparison of buffered and enteric-coated didanosine in HIV-infected children
Abstract 6.6: J.R. King, S. Nachman, R. Yogev, J. Hodge, G. Aldrovandi, B. Damle, E. Smith, A. Wiznia, E.P. Acosta.
Ten subjects completed pharmacokinetic evaluations for both formulations. Pharmacokinetic parameters of ddI EC 240mg/m2 were determined using noncompartmental methods. Median ddI AUC€, Cmax and Tmax following EC administration were 1879 ngxh/mL, 819 ng/mL and 4 hours, respectively. Modeled ddI pharmacokinetics produced a Cmax, AUC and Tmax of 627 ng/mL, 1969 ngxh/ml and 2.11h for the EC formulation and 830 ng/mL, 1536 ngxh/mL and 0.5 h for the buffered formulation. Systemic exposure was similar between buffered ddI and ddI EC in children. Cmax was approximately 28% lower and Tmax was prolonged approximately 4-fold following EC administration.
E. Seminari and colleagues from Italy compared the pharmacokinetics of NFV in HIV/HCV co-infected patients to HIV-positive patients without chronic liver disease.
Clinical pharmacokinetics of nelfinavir in HIV-HCV co-infected patietnts
Abstract 6.2: R. Maserati, E. Seminari, P. Villani, F. Marubbi, P. Zucchi, M.B. Regazzi.
Five HIV/HCV RNA+ patients and 7 HIV/HCV RNA- received NFV1250mg BID. A complete PK profile was obtained at steady-state during a dosing interval. Median AUC12h was 65.5 mg/mL for the co-infected patients compared with 33.25 mg/mL for the control group. Clearance was statistically lower in the HIV/HCV RNA+ patients (0.28 vs. 0.74 L/h/kg, p=0.0037).
Edit note: this is a small pilot study, but more studies like this are needed to try and evaluate the effect of liver disease on drug blood levels. Such studies might offer useful information on the use TDM to evaluate drug levels in the presence of HCV and liver damage. There was some question about the stage of liver disease in the patients studied. The study author and all the patients were reported to have had mild disease but the evaluation technique used was questioned its accuracy. Similar results might be found with other drugs if it were studied.
Numerous studies reported the pharmacokinetic interactions of various antiretrovirals.
Richard Bertz and colleagues from Abbott Laboratories presented data on the pharmacokinetic interaction between LPV/RTV and APV in healthy volunteers.
Assessment of the multiple dose pharmacokinetic interaction between Kaletra (Lopinavir/Ritonavir) and Amprenavir in healthy volunteers
Abstract 7.6: R. Bertz, C. Foit, D. Burt, A. Hsu, Y-L. Chiu, T. Chira, R. Wieboldt, L.A. Williams, G.R. Granneman, E. Sun.
Eleven healthy volunteers received LPV/r 400/100 mg BID on days 1-21. APV 750 mg BID was administered on days 12-21 and continued at 1200 mg BID alone on days 22-35. APV 750 mg BID with LPV/r produced a similar APV Cmax, but increased APV AUC and Cmin compared with APV 1200 mg BID alone. LPV concentrations were lower during co-administration with APV. (LPV AUC of 86.4 and 54.5 mgxh/mL; LPV Ctrough of 5.97 and 3.03 mg/mL; LPV Cmax 10.33 and 7.53 mg/mL, respectively).
Edit. Note: the clinical implications and potential dosing recommendations of combining Kaletra and amprenavir remain uncertain.
Nine HIV-infected, treatment-experienced men received 14 days of 2 NRTIs and either SQV 1000 mg/RTV 100mg BID or APV 600mg/RTV 100mg BID.
Simultaneous administration of Amprenavir and Saquinavir does not appear to lower plasma levels of either agent when coadministered with low-dose Ritonavir
Abstract 7.11: P.R. Wolfe, P.G. Anderson, S. Gunawan.
To investigate the dual PI drug interaction in salvage therapy, the authors examined the effect of amprenavir and saquinavir (soft-gel caps_ along with low-dose ritonavir on APV and SQV blood levels in a 16-week PK open-label, crossover PK study.
On day 15, patients in both groups received SQV/APV/RTV in addition to the NRTIs. Intensive PK evaluations were completed on days 14 and 28. AUC, Cmax and Cmin did not differ between day 14 and 28 for either APV or SQV. Authors concluded that APV and SQV do not influence plasma levels of either agent when co-administered with low-dose RTV. Authors reported seeing intersubject variation of blood APV and SQV levels.
Charles J.L. La Porte and colleagues from the Netherlands evaluated the PK and tolerability of LPV/r plus SQV in heavily pre-treated patients.
Lopinavir/Ritonavir plus Saquinavir in salvage therapy; pharmacokinetics, tolerability and efficacy
Abstract 7.14: C.J.L. La Porte, J.C. Wasmuth, D.M. Burger, J. Rockstroh.
Seven male patients received LPV/r 400/100mg and SQV 1000mg BID in addition to NRTIs. Blood samples were drawn pre-dose and up to 12 hours post-dose. Five of 7 subjects reported adverse events, these were mainly gastrointestinal and mild. Median LPV AUC12h, Cmax and Cmin were 88 mgxh/L, 9.9 mg/L and 4.8 mg/L, respectively and were comparable with product information. SQV AUC12h of 9.8 mgxh/L and Cmax of 1.6 mg/L was lower than AUC12h of 18.8 mgxh/L and Cmax of 3.7 mg/L from previous data. Cmin was 0.40 mg/L and comparable to previously reported data of 0.40 mg/L.
Edit. Note: the authors concluded that efficacy measured as a decline in viral load and an increase in CD4 count is encoraging.
One study evaluated the pharmacokinetic interactions between DLV, LPV and RTV in 34 healthy volunteers.
Pharmacokinetic interactions between Delavirdine (DLV), Lopinavir (LPV), and Ritonavir (RTV) during co-administration in healthy volunteers
Abstract 7.17: J.Q. Tran, M. Garrett, B. Hee, C. Ballow, C. Petersen.
Subjects in group 1(n=17) received LPV/r 400/100 mg BID from days 1 through 10 and LPV/r 266/66 mg + DLV 600 mg BID days 10 through 20. Subjects in group 2 (n=17) received DLV 600 mg BID for 10 days then received LPV/r 266/66 mg + DLV 600 mg BID on days 10 through 20. Both groups went through a washout period on days 14 through 21 and then received LPV/r 400/100 mg + DLV 600 mg BID for 10 days. Preliminary results show that DLV increased LPV Cmin, AUC, and Cmax by about 53%, 24%, and 13%, respectively. LPV/r 266/66 mg BID with DLV produced a 25% lower LPV AUC (49.6 vs. 65.4 mgxh/mL), Cmin (2.06 vs. 2.68 mg/mL) and Cmax (6.42 vs. 8.64 mg/mL) compared with LPV/r 400/100 mg BID alone. DLV also increased RTV exposure by about 50%. Both doses of LPV decreased DLV Cmin and AUC by approximately 30%. The authors concluded that in contrast to EFV, which has been shown to reduce LPV AUC and Cmin by about 25% and 44%, respectively, DLV increased LPV AUC and Cmin by 24% and 53%, respectively; thus avoiding the need to increase LPV/RTV dosing during coadministration. Further dose finding studies for this combination of antiretrovirals are needed.
Another area of research was the PK comparison of SQV hard gel capsules (SQV-hgc) with SQV soft gel capsules (SQV-sgc).
Two studies compared these formulations in different patient populations. The pharmacokinetics of RTV-enhanced SQV-hgc and SQV-sgc were evaluated in 13 HIV-infected Thai patients.
Invirase vs Fotovase, Once or Twice Daily
In the absence of ritonavir, Fortovase provides higher blood levels than Invirase. However, the following 2 preliminary small PK studies reported at the Pharmacology Workshop show Invirase may be just as effective as Fortovase when boosted with a low dose of 100 mg of ritonavir (Norvir). These results will be confirmed with further studies but they suggest Invirase may be preferable for use.
Pharmacokinetics (PK) of once daily Saquinavir-hard gel caps, Invirase, (SQV-HGC) and Saquinavir-soft gel caps, Fortovase, (SQV-SGC) boosted with Ritonavir (RTV) in HIV-1+ Thai patients: HIV NAT001.4 substudy
Abstract 1.2: P. Cardiello, T. Monhaphol, A. Mahanontharit, R.P. van Heeswijk, D. Burger, K. Ruxrungtham, J. Lange, D. Cooper, P. Phanuphak.
Subjects received SQV-sgc 1600mg/RTV 100mg BID QD with dual NRTI therapy for 1 week followed by a change to SQV-hgc 1600mg/RTV 100mg BID for 1 week. A 12-hour PK profile was completed. Differences between SQV-hcg AUC (50.0 mgxh/L) and SQV-sgc AUC (35.5 mgxh/L) were not statistically different (p=0.056). Median Cmin for SQV-hgc and SQV-sgc were 0.21 and 0.07 mg/L, respectively.
Edit note: All patients (n=13) were using Fortovase (soft-gel caps)/r 1600/100 mg once daily + 2 NRTIs for 48 weeks or longer, and had <50 copies/ml of viral load and CD4s >350. The Invirase Cmax was about the same as for Fortovase. The Invirase blood levels (Cmax, Cmin, AUC) were at least as good as those for Fortovase. Since the patients were already on Fortovase for 48 weeks, you have to assume they were able to tolerable the medication. The authors proposed an explanation for the similar exposure levels for Invirase and Fortovase. The delayed absorption of Invirase may extend the time frame of the interaction with ritonavir, therefore increasing AUC and Cmin. The authors suggested possible advantages for patients of Invirase/r over Fortovase/r: smaller pill size, better tolerability.
Another study compared the PK of SQV-sgc/RTV with SQV-hgc/RTV in healthy volunteers.
Invirase (hard-gel caps) Has Same Blood Levels as Fortovase (soft-gel caps), When Used With 100 mg of Ritonavir Twice Daily
"Comparative inter- and intraindividual variability of Saquinavir trough levels in subjects receiving twice daily Fortovase/Ritonavir (1000/100)"

Abstract 7.18: M. Kurowski, T. Sternfield, A. Hill, C. Moecklinghof.
Subjects received either SQV-sgc or SQV-hgc, both dosed at 1000 mg BID, in addition to RTV 100 mg BID for 10 days and a PK evaluation was performed. Subjects were then switched at day 10 to the opposite formulation of SQV plus RTV, at which a PK evaluation was performed at day 20. PK parameters were estimated by non-compartmental methods. SQV-hgc resulted in a significantly higher SQV Cmin24 (232 vs. 166 ng/mL, p=0.0143) and AUC24 (15798 vs. 11655 ngxh/mL, p=0.0043) compared with SQV-sgc. SQV-hgc was also better tolerated with less diarrhea and abdominal distention. The Cmax for the Invirase/r regimen was 1228 ng/L and for the Fortovase/r regimen it was 983 ng/L.
Kurowsky reported that the combination of Invirase/r was better tolerated than Fortovase/r, with diarrhea and abdominal distension occurring less frequently. They suggested the better tolerability may be due to capmul, the glyceride excipient component of Fortovase, which is not present in Invirase. The authors suggested that for patients taking 1000mg/100mg Fortovase twice daily or other dose regimens who have GI side effects, a switch to Invirase/r at the same dosage may be an additional treatment option.
It is clear that enhancing PI plasma concentrations with RTV improves the pharmacokinetic profile, decreases pill burden, and in some cases improves tolerability of the regimen. Those of us involved with describing the clinical pharmacology of these drugs need to ensure that our data is as robust as possible. In some studies it may be prudent to collect only trough levels, depending upon the objectives of the trial. In most cases, however, collecting more intensive PK data, or at least datasets that can be described by appropriate models, will yield more enlightening information that can then be confirmed or refuted by additional studies.
Discussions on Protein Binding
A considerable amount of time was spent during the meeting discussing the relevance of protein binding of antiretrovirals. It is important to keep in mind that these drugs bind to AAG, HS, maybe HSA and 10% FCS. Varying the concentrations of these proteins will obviously affect the observed shift in IC50. Consistency across labs would shed more light on the influence of protein binding or viral susceptibility.
If a drug has activity in vivo (in patients), then the degree of protein binding is not a major factor. However, if a drug is active in vitro, protein binding must be considered since the drug may not show activity in patients (i.e. the Searle protease inhibitor). The primary interest in protein binding lies in the interpretation of susceptibility tests. An IC50 in vitro is not the same as an IC50 in vivo if a drug is highly protein bound. So, we need to ensure that susceptible data are interpreted with protein binding data in mind. Otherwise, no comparisons can be made between IC50 and plasma drug concentrations or across different drugs.